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Aprea Therapeutics Announces Positive Results from Phase 2 Trial of Eprenetapopt + Azacitidine … – The Bakersfield Californian

By daniellenierenberg

58% relapse free survival at 1 year post-transplant79% overall survival at 1 year post-transplant

BOSTON, July 21, 2021 (GLOBE NEWSWIRE) -- Aprea Therapeutics, Inc. (Nasdaq: APRE), a biopharmaceutical company focused on developing and commercializing novel cancer therapeutics that reactivate mutant tumor suppressor protein, p53, today announced positive results from its Phase 2 trial evaluating eprenetapopt with azacitidine for post-transplant maintenance therapy in patients with TP53 mutant MDS and AML.

In 33 patients enrolled in the trial, the relapse free survival (RFS) at 1 year post-transplant was 58% and the median RFS was 12.1 months. The overall survival (OS) at 1 year post-transplant was 79%, with a median OS of 19.3 months. Prior clinical trials evaluating post-transplant outcomes in TP53 mutant MDS and AML patients have reported a 1-year post-transplant RFS of ~30% and a median OS of ~5-8 months. In addition, the post- transplant regimen of eprenetapopt and azacitidine was well tolerated among patients in the clinical trial. The Company plans to discuss the data from this Phase 2 clinical trial with the U.S. Food and Drug Agency (FDA) in the second half of 2021 and expects to present data at a future scientific or medical conference.

The post-transplant RFS and OS data with eprenetapopt and azacitidine maintenance therapy in these very difficult-to-treat TP53 mutant MDS and AML patients are incredibly exciting, said trial principal investigator Asmita Mishra, M.D., of the H. Lee Moffitt Cancer Center and Research Institute. Although transplant is currently the only potentially curative treatment for patients with TP53 mutant MDS and AML, the risk of relapse with current standard of care remains unacceptably high and the median OS post-transplant is very limited at 8 months or less. Post-transplant maintenance therapy with eprenetapopt and azacitidine could, if approved, represent a new treatment paradigm that meaningfully improves outcomes for these patients with limited treatment options.

About Aprea Therapeutics, Inc.

Aprea Therapeutics, Inc. is a biopharmaceutical company headquartered in Boston, Massachusetts with research facilities in Stockholm, Sweden, focused on developing and commercializing novel cancer therapeutics that reactivate mutant tumor suppressor protein, p53. The Companys lead product candidate is eprenetapopt (APR-246), a small molecule in clinical development for hematologic malignancies and solid tumors. Eprenetapopt has received Breakthrough Therapy, Orphan Drug and Fast Track designations from the FDA for myelodysplastic syndromes (MDS), Orphan Drug and Fast Track designations from the FDA for acute myeloid leukemia (AML), and Orphan Drug designation from the European Commission for MDS and AML. APR-548, a next generation small molecule reactivator of mutant p53, is being developed for oral administration. For more information, please visit the company website at

The Company may use, and intends to use, its investor relations website at as a means of disclosing material nonpublic information and for complying with its disclosure obligations under Regulation FD.

About p53, eprenetapopt and APR-548

The p53 tumor suppressor gene is the most frequently mutated gene in human cancer, occurring in approximately 50% of all human tumors. These mutations are often associated with resistance to anti-cancer drugs and poor overall survival, representing a major unmet medical need in the treatment of cancer.

Eprenetapopt (APR-246) is a small molecule that has demonstrated reactivation of mutant and inactivated p53 protein by restoring wild-type p53 conformation and function thereby inducing programmed cell death in human cancer cells. Pre-clinical anti-tumor activity has been observed with eprenetapopt in a wide variety of solid and hematological cancers, including MDS, AML, and ovarian cancer, among others. Additionally, strong synergy has been seen with both traditional anti-cancer agents, such as chemotherapy, as well as newer mechanism-based anti-cancer drugs and immuno-oncology checkpoint inhibitors. In addition to pre-clinical testing, a Phase 1/2 clinical program with eprenetapopt has been completed, demonstrating a favorable safety profile and both biological and confirmed clinical responses in hematological malignancies and solid tumors with mutations in the TP53 gene.

A pivotal Phase 3 clinical trial of eprenetapopt and azacitidine for frontline treatment of TP53 mutant MDS has been completed and failed to meet the primary statistical endpoint of complete remission. A Phase 1/2 clinical trial of eprenetapopt with venetoclax and azacitidine for the frontline treatment of TP53 mutant AML met the primary efficacy endpoint of complete remission. Additional clinical trials in hematologic malignancies and solid tumors are ongoing. Eprenetapopt has received Breakthrough Therapy, Orphan Drug and Fast Track designations from the FDA for MDS, Orphan Drug and Fast Track designations from the FDA for AML, and Orphan Drug designation from the European Medicines Agency for MDS and AML.

APR-548 is a next-generation small molecule p53 reactivator. APR-548 has demonstrated high oral bioavailability, enhanced potency relative to eprenetapopt in TP53 mutant cancer cell lines and has demonstrated in vivo tumor growth inhibition following oral dosing of tumor-bearing mice.

About MDS

Myelodysplastic syndromes (MDS) represent a spectrum of hematopoietic stem cell malignancies in which bone marrow fails to produce sufficient numbers of healthy blood cells. Approximately 30-40% of MDS patients progress to acute myeloid leukemia (AML) and mutation of the p53 tumor suppressor protein is thought to contribute to disease progression. Mutations in p53 are found in up to 20% of MDS and AML patients and are associated with poor overall prognosis. There are no currently approved therapies specifically for TP53 mutant MDS or AML patients.

About AML

AML is the most common form of adult leukemia, with the highest incidence in patients aged 60 years and older. AML is characterized by proliferation of abnormal immature white blood cells that impairs production of normal blood cells. AML can develop de novo or may arise secondary to progression of other hematologic disorders or from chemotherapy or radiation treatment for a different, prior malignancy; secondary AML carries a worse prognosis than de novo AML. Mutations in TP53, which are associated with poor overall prognosis, occur in approximately 20% of patients with newly diagnosed AML, more than 30% of patients with therapy-related AML and approximately 70-80% of patients with complex karyotype.

Forward-Looking Statement

Certain information contained in this press release includes forward-looking statements, within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, related to our study analyses, clinical trials, regulatory submissions, and projected cash position. We may, in some cases use terms such as future, predicts, believes, potential, continue, anticipates, estimates, expects, plans, intends, targeting, confidence, may, could, might, likely, will, should or other words that convey uncertainty of the future events or outcomes to identify these forward-looking statements. Our forward-looking statements are based on current beliefs and expectations of our management team that involve risks, potential changes in circumstances, assumptions, and uncertainties. Any or all of the forward-looking statements may turn out to be wrong or be affected by inaccurate assumptions we might make or by known or unknown risks and uncertainties. These forward-looking statements are subject to risks and uncertainties including risks related to the success and timing of our clinical trials or other studies, risks associated with the coronavirus pandemic and the other risks set forth in our filings with the U.S. Securities and Exchange Commission. For all these reasons, actual results and developments could be materially different from those expressed in or implied by our forward-looking statements. You are cautioned not to place undue reliance on these forward-looking statements, which are made only as of the date of this press release. We undertake no obligation to publicly update such forward-looking statements to reflect subsequent events or circumstances.

Source: Aprea Therapeutics, Inc.

Corporate Contacts:

Scott M. Coiante Sr. Vice President and Chief Financial Officer 617-463-9385

Gregory A. Korbel Sr. Vice President and Chief Business Officer 617-463-9385

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Aprea Therapeutics Announces Positive Results from Phase 2 Trial of Eprenetapopt + Azacitidine ... - The Bakersfield Californian

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Chronic Inflammation Can Serve as A Key Factor in The Development of Leukemia, Other Blood Cancers – Pharmacy Times

By daniellenierenberg

The first paper, titled PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress, takes a look at the effect of inflammation on the transcription factor PU.1 and its effect on the production of hematopoietic stem cells (HSCs), or the immature cells found in the bone marrow that can turn into blood cells, according to the study author James Chavez, BS.

Second corresponding author Eric Pietras, PhD, CU Cancer Center Member, said the research from Chavez challenged his previous understanding of how inflammation impacts HSCs.

We thought that introducing a proinflammatory cytokine like Interleukin (IL)-1 would make hematopoietic stem cells proliferate, because when you have inflammation, the body typically interprets it as a signal to produce more white blood cells to fight off an infection or injury, Pietras said, in a CU interview.

However, he and his team discovered that in the presence of IL-1, genes that control the creation of additional hematopoietic stem cells were turned off rather than on, specifically genes related to the synthesis of proteins, were the key of building new cells. I think some of the best science is that which disproves your own notions and dogmas, Pietras said in the CU interview.

The team ended up finding a transcription factor called PU.1 that represses protein synthesis genes in HSCs during periods of inflammation.

That made us wonder what would happen if we got rid of PU.1, Pietras said in the CU interview. He and his team used genetic mouse models that reduced the amount of PU.1 in the HSCs or remove it altogether, uncovering that when PU.1 is reduced or removed, inflammation caused by the introduction of IL-1 triggers the proliferation and expansion of HSCs.

Our findings point to an interesting mechanism for how inflammation can trigger differences in cell fitness when normal HSCs have to compete with HSCs harboring oncogenic mutations that are known to disable or reduce PU.1, Pietras said in the CU interview. In this case, those PU.1- deficient HSCs act like normal cells as long as there's no inflammation. But as soon as you trigger an inflammatory response, it's like throwing gasoline on a fire. The HSCs with loss of PU.1 expand because there is no longer a mechanism to turn their protein synthesis off. And when that happens, you get uncontrolled growth of the PU.1-deficient hematopoietic stem cells, which can eventually lead to leukemia, a type of blood cancer.

The second paper, titled Chronic interleukin-1 exposure triggers selection for Cebpa-knockout multipotent hematopoietic progenitors, co-led by DeGregori and Pietras, looks at the impact of the proinflammatory cytokine IL-1 on hematopoietic stem and progenitor cells (HSPCs).

One of the primary goals, according to DeGregori, was to better understand the factors that determine what kind of mature blood cells are produced from our blood stem cells, or the HSPCs, in response to chronic inflammation. Mouse models were studied by injecting with IL-1 to copy an infection and cause inflammation. This action impacted blood cell production towards making granulocytes, which is a type of white blood cell that helps the immune system fight infections, according to the study authors.

The team also found that inflammation seemed to alter selection in the HSPCs toward oncogenic mutations of the Cebpa gene that are often found in leukemia.

"Our data would suggest that old age, and the inflammation associated with it, could contribute to the increased leukemia rates that occur in the elderly, DeGregori said in the CU interview. For every good process that happens in your body, such as fighting infection, there can also be adverse reactions that create risk. And we think inflammation creates some level of risk, particularly if it's a chronic situation.

DeGregori added that the most widespread cause of inflammation is old age, and examples of conditions that could cause long-term inflammation include arthritis and chronic infections, such as colitis.

"When we get old, many of us become chronically inflamed, DeGregori said in the CU interview. Not everyone experiences the same level of inflammation, but higher inflammation tends to coincide with worse outcomes for people. Our data would suggest that old age, and the inflammation associated with it, could contribute to the increased leukemia rates that occur in the elderly, particularly acute myeloid leukemia (AML).

DeGregori and Pietras note that solving this issue is more complicated than wiping out inflammation altogether.

Inflammation is critically important for surviving infections, DeGregori said in the CU interview. Over evolutionary time, dying from infection was a major risk, so we evolved inflammation as a mechanism to avoid that. On the other hand, we've shown that chronic inflammation could promote selection for oncogenic events, such as through inhibition of Cebpa.

According to Pietras, the next step is to apply these findings to human biology.

I think there are a few different implications for the work, Pietras said in the CU interview. One is that we're learning more about when and where stem cells first gain mutations and the extent to which inflammation can impact the capacity of these mutant HSCs to eventually initiate leukemia. What this tells us is that if we can intervene at an early stage, we may be able to reduce the risk of getting blood cancer.

The studies helped to show that both preventive measures for those at higher risk of developing cancer and treatments for those who are already diagnosed could potentially be improved by addressing bad inflammation while maintaining the immune systems ability to function, according to study authors.

"We don't want to limit someone's risk of getting leukemia and at the same time increase their risk of dying from an infection, DeGregori said in the CU interview. But the more we learn about it, the better we might get at finding that happy balance.


Gleaton V. Two Studies by CU Cancer Center Researchers Explore Link Between Inflammation and Leukemia. University of Colorado Cancer Center. Published June 28, 2021. Accessed July 1, 2021.

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Impact of NK cell-based therapeutics for Lung Cancer Therapy | BTT – Dove Medical Press

By daniellenierenberg


Lymphoid non-T cells that can kill virally infected and tumor cells were described more than four decades ago and termed natural killer (NK) cells.1 NK cells can attack tumor cells without priming and their activity depends on a range of stimulatory and inhibitory receptors.2,3 NK cells comprise about 515% of the human peripheral blood mononuclear cells (PBMCs) and are part of the native immune system that screen cell membranes of autologous cells for a reduced expression of MHC class I molecules and increased expression of cell stress markers.4,5 NK cells mediate the direct and rapid killing of freshly isolated human cancer cells from hematopoietic and solid tumors.6,7 (Figure 1) NK cells in human peripheral blood, bone marrow and various tissues are characterized by the absence of T cell receptors (TCR) and the corresponding CD3 molecules as well as by the expression of neural cell adhesion molecule (NCAM/CD56).8 Human NK cells are generated from multilineage CD34+ hematopoietic progenitors in the bone marrow and their maturation occurs at this site of origin as well as in the lymphoid organs but not in thymus.9 In blood, NK cells show a turnover time of approximately 2 weeks with a doubling within 13.5 days in vivo and in vitro cytokine stimulation of peripheral blood NK cells can result in expansion with a median of 16 (range 1130) population doublings.10

Figure 1 NK cells and other immune cells in the tumor microenvironment. NK cells of the CD56dim CD16+ phenotype secrete interferon- (IFN-), which increases the expression of MHC class I of tumor cells, enhancing the presentation of tumor antigens to T cells. Inhibitory checkpoint molecules expressed by NK cells can be blocked using specific monoclonal antibodies (ICIs). NK cells of the CD56bright CD16- phenotype recruit dendritic cells (DCs) to the tumor microenvironment (TME) and drive their maturation via chemokine ligands CCL5, XCL1 and FMS-related tyrosine kinase 3 ligand (FLT3L). DCs in turn stimulate NK and T cells via membrane-bound IL-15 (mbIL-15) and 41BBL secretion. Eventually, NK cells lyse tumor cells resulting in release of cancer antigens, which are then presented by DCs, to provoke specific T cell activation in relation with MHC class I molecules. The immunotherapeutic effect of NK cells includes the removal of immunosuppressive MDSCs.

NK cells are not only present in peripheral blood, lymph nodes, spleen, and bone marrow but they can also migrate to sites of inflammation in response to distinct chemoattractants. The majority of CD56dim subpopulation of the whole NK cells in peripheral blood (approximately 90%) exhibits high expression of the Fc receptor FcRIII (CD16), killer cell immunoglobulin-like receptors (KIRs) and perforin-mediated cytotoxicity whereas a minor population of CD56bright CD16- KIR- CD94/NKG2A+ (approximately 515%) of NK cells is primarily producing cytokines, including IFN- and TNF-1113 These two NK cell populations have been termed conventional NK cells in contrast to distinct tissue-resident NK cell populations localizing to liver, lymphoid tissue, bone, lung, kidney, gut and uterine tissue as well as distinct adaptive NK cell populations.14 However, CD56 and CD16 are not specific for NK cells and, furthermore, the heterogeneous tissue-resident populations show expression of adhesion molecules and CD69 and may represent an immature NK cell type. Adaptive NK cells are observed in connection with viral infections and exhibit memory cell-like properties. Overall, a wide diversity of receptor expressions of NK cells has been observed and, so far, the function of many of these subpopulations has not been fully characterized.

NK cells can eliminate target cells controlled by signals derived from activating (eg, NCRs or NKG2D) and inhibitory receptors (eg, KIRS or NKG2A).1517 Normal host cells are protected from NK cells attacks through inhibitory KIRs, that identify the self-MHC class I molecules.15 In particular, the germline-encoded NK receptors include the activating receptors NKG2D, DNAM-1, the natural killing receptors NKp30, NKp44, NKp46, and NKp80, the SLAM-family (Signaling Lymphocyte Activating Molecule) receptors for the elimination of hematopoietic tumor cells and the inhibitory KIRs.18 The activating signaling molecules promote tumor cell killing, cytokine production, immune cell activation, and proliferation and the NKpXX receptors, when engaged, all trigger alterations of the cellular calcium flux and NK cell-mediated killing and secretion of IFN- (Figure 1).

The interaction between KIRs and self-MHC molecules governs the maturation of NK cell, a process termed licensing.11,19,20 As alternative of MHC downregulation, cancer cells may be recognized by the overexpression of binding molecules for activating NK cell receptors. Ligands for the activating NKG2D receptor, such as MHC class I polypeptide-related sequence A (MICA), MICB and others are presented by cancer cells preferentially in response to cellular stress.21 A separate mechanism known as antibody-dependent cell cytotoxicity (ADCC) results in elimination of antibody-coated cell via the CD16 FcRIII receptor.22

NK cell-mediated lysis of target cells is mainly achieved through the release of the cytotoxic effector perforin and granzymes A and B but NK cells also produce a range of cytokines, both proinflammatory and immunosuppressive, such as IFN-, TNF- and IL10, respectively, as well as growth factors such as granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF) and IL-3 (Figure 1). CD56dim NK cells can produce very rapidly IFN- within 2 to 4 hours after triggering through NKp46 and NKp30 activating receptors (ARs).12,13 NK cellderived cytokine production impacts dendritic cells, macrophages and neutrophils and empower NK cells to regulate subsequent antigen-specific T and B cell responses. Activated NK cells lose CD16 (FcRIII) and CD62 ligand through the disintegrin and metalloprotease 17 (ADAM17), and inhibition of this protease enhances CD16-mediated NK cell function. Cytokine stimulation also downregulates CD16 and upregulates CD56 expression. Moreover, certain cytokines can greatly enhance the cytotoxicity and cytokine production of the CD162 CD56bright and CD161 CD56dim NK cell subsets, respectively.23,24

In cancer patients, NK cells target cells low/deficient of MHC-class I or bearing altered-self stress-inducible proteins.17,25 Besides tumor cell killing through release of perforin and granzyme and secretion of immunoregulatory mediators such as nitric oxide (NO) effects cell death mediated by TNF-family members such as Fas-L or TRAIL. The degree of tumor infiltration of NK cells seems to have prognostic value in gastric carcinoma, colorectal carcinoma and lung carcinomas, thus indicating a protective role of the NK cell infiltrate.26,27 NK cell infiltration of tumors depends on their expression of heparinase.28 NK cells may further attract T cells to the tumor region and elevate inflammatory responses through secretion of cytokines and chemokines.29 Furthermore, NK cells have been suggested to suppress metastasis through elimination of circulating tumor cells (CTCs).30

NK cells seem well suited for anticancer immunotherapy and cells for clinical administration can be isolated from peripheral or umbilical cord blood. Peripheral blood NK cells are prepared by leukapheresis and further enriched by density gradient centrifugation (Figure 2). Subsequently, the combination of T cell depletion with CD56 cell enrichment yields highly purified NK cell populations.31 NK cells gained from peripheral blood of healthy persons are typically in a resting state and can be activated by exposure to IL-2. However, supplementation with IL-2 and infusion to cancer patients has resulted in severe side effects, such as vascular leak syndrome and liver toxicity.32 Studies with native autologous NK cells have yielded disappointing results. The most efficient NK cell expansion was observed with K562 NK target cells co-expressing membrane-bound IL-15 (mbIL-15) and 41BBL.31 This technique yields enough NK to provide cells for at least four infusions at 50 million cells/per kg from one leukapheresis product observing GMP conditions.31 However, many mechanisms mediate NK cell suppression in the tumor microenvironment (TME), several of which also impair T cell responses.33,34 In case of NK cells, NKG2D ligand release can occur by shedding and these soluble ligands prevent NK cell-tumor cell interaction and the cytotoxic response.35,36

Figure 2 Isolation, activation and propagation of allogeneic NK cells. Peripheral blood mononuclear cells (PBMCs) are prepared from healthy donors by leukapheresis. PBMC depletion of CD3+ T cells, prevents GvHD after infusion and further purification is achieved by positive CD56+ cell selection. These cell preparations are infused or activated with IL-2 or a mixture of IL-12, IL-15 and IL-18. Another method for NK cell stimulation involves ex vivo coculture with the K562 cell line expressing membrane-bound IL-15 (mbIL-15) and 41BBL that is irradiated to abolish expansion. Umbilical cord blood NK cells can be used similar to peripheral blood NK cells or enriched for CD34+ hematopoietic progenitors, followed by differentiation to NK cells. NK cells can be gained from induced pluripotent stem cells (iPSCs) via successive hematopoietic and NK cell differentiation, followed by stimulation with cells expressing mbIL-21. Before infusion of allogeneic NK cells, patients receive lymphodepleting chemotherapy to facilitate temporary engraftment of the infused NK cells.

In summary, NK cells are functional in tumor surveillance and can be manipulated by artificial activation techniques to present a highly effective anticancer tool against hematopoietic malignancies and, dependent on successful further rearming and mobilization, against solid tumors in the future.

The lungs are frequently challenged by pathogens, environmental damages and tumors and contain a large population of innate immune cells.37,38 Involvement of NK cells in lung diseases, such as cancer, chronic obstructive pulmonary disease (COPD), asthma and infections, has been amply reported.39 Chronic inflammation drives the irreversible obstruction of the lung function in COPD and local NK cells show hyperresponsiveness in COPD and kill autologous lung CD326+ epithelial cells.40 Therefore, targeting NK cells may represent a novel strategy for treating COPD. Furthermore, NK cells from cigarette smoke-exposed mice produce higher levels of IFN- upon stimulation with cytokines or toll-like receptor (TLR) ligands.41

Lung NK cells account for approximately 1020% of local lymphocytes and have migrated to the lungs from bone marrow.42 These cells exhibit the phenotype of the CD56dim CD16+ subset and are located in the parenchyma.43 Lung NK cells show major differences in phenotype and function to those from other tissues and, for example, KIR-positive NK cells and differentiated CD57+ NKG2A cells are found in higher numbers in the lungs compared to matched peripheral blood.37,38 In vivo, human lung NK cells respond poorly to activation by target cells in comparison to peripheral blood NK cells, most likely due to suppressive effects of alveolar macrophages and soluble factors in the fluid of the lower respiratory tract.44 The presence of hypofunctional NK cells seems to regulate the pulmonary homeostasis in the presence of constantly irritation by environmental and autologous antigens.

Unlike other tissues, the lung NK cell diversity and its acquisition have been very little studied, especially regarding the resident lung populations. Although the majority of lung NK cells are of a non-tissue-resident phenotype, a small CD56bright CD49a+ lung NK cell subset has been found.45 NK cell diversity occurs for the main resident population within the lung, namely CD49a+CD56bright CD16 NK cells that can be split into four different resident subpopulations according to the residency markers CD69 and CD103.47 The CD69+CD103+ subset is the most important as compared to single positive or double negative subsets. The respective significance of these subsets in terms of ontogeny, differentiation, or functionality remains to be characterized.

The CD16 NK cells in the human lung comprises a heterogeneous cell population and the CD69+CD49a+CD103 and CD69+CD49a+CD103+ tissue-resident NK cells are clearly distinct from other NK cell subsets in the lung and other tissues, whereas CD69spCD16 NK cells (lacking expression of CD49a and/or CD103) largely represent conventional CD69CD16 NK cells.47 Furthermore, lung tissue-resident NK cells are functionally competent and constitute a first line of defense in the human lung. Protein and gene expression signatures of CD16 NK cell subsets correlated with distinct patterns of expression of CD69, CD49a, and CD103 and corroborated the CD69+CD49a+CD103 and CD69+CD49a+CD103+ NK cells as tissue-resident NK cells.48 In contrast, CD69spCD16 NK cells are more similar to CD69CD16 NK cells and showed lower expression of genes associated with tissue-residency.

On the course of NK cell differentiation less differentiated NK cells are hypofunctional but respond stronger to cytokine stimulation and more differentiated NK cells exert more potent ADCC-dependent cell killing.46,49 The early activation antigen CD69 is expressed on a wide range of tissue-resident lymphocytes, including T cells and NK cells, and promotes retention of the cells in the tissue.38,50 Highly differentiated and hypofunctional CD69+ CD56dim CD161+ NK cells constitute the dominant NK cell population in the human lung. In summary, these results indicate that the human lung is mainly populated by NK cells migrating between lung and blood, rather than by CD69-positive tissue-resident cells. The mechanisms controlling this distribution of the lymphocyte populations is not known but may comprise changes in the homing of NK cells, increased apoptosis of NK cells and increased expansion or recruitment of tissue-resident T cells.

Although the incidence of lung cancer is declining, the survival rates remain poor due to a lack of early detection and only recent progress in targeted cancer therapies that are still only feasible for a limited subpopulation of patients.51,52 The host of immune cells involved in lung cancer include CD4+ and CD8+ T lymphocytes, neutrophils, monocytes, macrophages, innate lymphoid cells (ILCs), dendritic cells and NK cells. In lung cancer patients, peripheral NK cell cytotoxicity and INF- production was reported to be reduced.5356 Especially, a lower cytotoxic activity in NK cells was observed in smokers due to the suppression of the induction of IL-15 and IL-15-mediated NK cell functions in human PBMCs.57 Furthermore, the granzyme B release by NK cells from lung cancer tissue is lower compared to adjacent normal tissue.58 Additionally, peripheral NK cells of NSCLC patients are present in lower cell numbers and display a distinctive receptor expression with downregulation of NKp30, NKp80, CD16, DNAM1, KIR2DL1, and KIR2DL2, but upregulation of NKp44, NKG2A, CD69, and HLA-DR. Furthermore, low levels of IFN- and CD107a result in impaired cytotoxicity and promotion of tumor growth.54,59,60 The CD56bright CD16-NK cell subset is highly enriched in the tumor infiltrate and show activation markers, including NKp44, CD69, and HLA-DR.5961 However, the release of soluble factors by NSCLC tumor cells inhibit the activity of granzyme B and perforin and the induction of IFN- in intratumoral NK cells and suggest a local inhibition of NK cells by the NSCLC TME.62 T cell immune checkpoint molecules programmed cell death 1 (PD-1), cytotoxic T lymphocyte antigen 4 (CTLA4), lymphocyte activation gene 3 protein (LAG3) and TIM3 are expressed by subpopulations of NK cells and might reduce NK antitumor responses. In solid tumors, vascular supply may be ineffective causing hypoxia and low nutrient levels in the TME that may impair NK cell metabolism and antitumor cytotoxicity as demonstrated in lung experimental animal models.63,64 Additionally, the CD56bright CD16- NK cells enhance protumor neoangiogenesis through secretion of VEGF, placental growth factor and IL-8/CXCL8.65

Small cell lung cancer (SCLC) is a pulmonary neuroendocrine cancer linked to smoking that has a dismal prognosis and invariably develops resistance to chemotherapy within a short time.66 Despite a high tumor mutational burden, immune checkpoint inhibitors show minor prolongation of survival in SCLC patients.66,67 In particular, Nivolumab (anti-PD1 antibody) was approved for third-line treatment and the combination of atezolizumab (anti-PDL1 antibody) with carboplatin and etoposide was approved for first-line treatment of disseminated SCLC, resulting in minor survival gains.68,69 NK cells are critical in suppressing lung tumor growth and while low MHC expression would make SCLC resistant to adaptive immunity, this should make SCLCs susceptible to NK cell killing.64,70 In comparison to the peripheral blood NK cells of healthy individuals, the NK cells of SCLC patients are present in equal cell counts but exhibit lower cytotoxic activity, downregulation of NKp46 and perforin expression.55 Lack of effective NK surveillance seems to contribute to SCLC progress, primarily through the reduction of NK-activating ligands (NKG2DL). SCLC primary tumors possess very low levels of NKG2DL mRNA and SCLC lines largely fail to express NKG2DL at the protein level.66,71 Accordingly, restoring NKG2DL in experimental models suppressed tumor growth and metastasis in a NK cell-dependent manner. Furthermore, histone deacetylase (HDAC) inhibitors induced NKG2DL re-expression and resulted in tumor suppression by NK and T cells. Actually, SCLC and neuroblastoma are the two tumor types with lowest NKG2DL-expression. In conclusion, epigenetic silencing of NKG2DL results in a defect of NK cell activation and immune escape of SCLC and neuroblastoma. Poor immune infiltrates in SCLC tumors combined with reduced NK and T cell recognition of the tumor cells seem to contribute to immune resistance of SCLCs.72

A majority of NSCLC patients do not benefit from the current IC-directed immunotherapy. CD56dim CD16+ NK cells comprise the majority of NK cells in human lungs and express KIRs and a more differentiated phenotype compared with NK cells in the peripheral blood.38,73 However, human lung NK cells were hyporesponsive toward target cell stimulation, irrespective of priming with IFN-. NK cells are activated by MICA and MICB expressed by stressed tumor cells and are recognized by NK cell receptors NKG2D.74 Preclinical studies show that NKG2A or TIGIT blockade enhances antitumor immunity mediated by NK cells.2 However, the poor infiltration of NK cells into solid tumors, alterations in activating/inhibitory signals and adverse TME conditions decrease the NK-mediated killing. NK cells can be inactivated by different cells such as Tregs and MDSCs but also by soluble mediators such as adenosine.75,76 Adenosine represents one of the most potent immunosuppressive factors in solid tumors that is produced in the tumor stroma by degradation of extracellular ATP.7779 ATP and ADP are degraded by membrane-expressed ectonucleotidases such as CD39 and enhance the influx and the suppressive capacity of Tregs and MDSCs in solid tumors. NK cells are strongly involved in eliminating circulating tumor cells (CTCs), but their activity can be inhibited by soluble factors, such as TGF- derived from M2 macrophages.80,81 One approach uses cytokines to selectively boost both the number as well as the efficacy of anti-tumor functions of peripheral NK cells.82 The gene signature of NK cell dysfunction in human NSCLC revealed an altered migratory behavior with downregulation of the sphingosine-1-phosphate receptor 1 (S1PR1) and CX3C chemokine receptor 1 (CX3CR1).83 Additionally, the expression of the immune inhibitory molecules CTLA-4 and killer cell lectin like receptor (KLRC1) were elevated in intratumoral NK cells and CTLA-4 blockade could partially restore the impaired MHC class II expression on dendritic cell (DC). In summary, the intratumoral NK dysfunction can be attributed to direct crosstalk between tumor and NK cells, activated platelets and soluble factors, such as TGF-, prostaglandin E2, indoleamine-2,3-dioxygenase, adenosine and IL-10.19,26,54,83 In addition, a specific migratory signature could explain the exclusion of NK cells from the tumor interior. NK cells in NSCLC distribute to the intratumoral fibrous septa and to the borders between tumor cells and surrounding stroma.54,59 It has been suggested that a barrier of extracellular matrix proteins may be responsible for the restriction of NK cells primarily to the tumor stroma, such preventing direct NK celltumor cell interactions.84,85 In contradiction, ultrastructural investigations demonstrated NK cells are rather flexible and capable of extravasation and intratumoral migration.59 CD56bright CD162+ NK cells express CCR5 that is known to mediate the chemoattraction of specific leukocyte subtypes and explain their accumulation in tumor tissues.13 Infiltration of the tumors by NK cells was reported to be linked with a favorable prognosis in lung cancer.26,86 However, Platonova et al reported that NK cell infiltration lacks any correlation with clinical outcomes in NSCLC.47,54 The poor prognostic significance of NK cells in NSCLC seems to be associated with the intratumoral NK cell dysfunction in patients with intermediate or advanced-stage tumors.

It would be of great importance to target chemokine receptors on NK cells to enable them to enter tumor tissues. NK cells acquire inhibitory functions within the TME, the reversion of which will enable NK cells to activate other immune cells and exert antitumor cytotoxic functions.87 In addition, several clinical trials based on NK cell checkpoints are ongoing, targeting KIR, TIGIT, lymphocyte-activation gene 3, TIM3 and KLRC1.88 NK cell dysfunction favors tumor progress and restoring NK cell functions would represent an important potential strategy to inhibit lung cancer. These approaches include the activation of NK cells by exposing to interleukins such as IL-2, IL-12, IL-15, IL-18, the blockade of inhibitory receptors of NK cells by targeting NKG2A, KIR2DL1 and KIR2DL2 as well as the enhancement of NK cell glycolysis by inhibition of fructose-1,6-bisphosphatase 1 and altering the immunosuppressive TME by neutralization of TGF-.37,53 Pilot clinical trials of NK cell-based therapies such as administration of cytokines, NK-92 cell lines and allogenic NK cell immunotherapy showed promising outcomes on the lung cancer survival with less adverse effects. However, due to the lack of larger clinical trials, the NK cell targeting strategy has not been approved for lung cancer treatment so far.

Most of studies regarding NK cell-based immunotherapy have been performed in hematologic malignancies. However, there are increasingly data available that show that NK cells can selectively recognize and kill cancer stem cells in solid tumors.89 Furthermore, Kim et al showed the essential role of NK cells in prevention of lung metastasis.90 Additionally, Zhang et al studied the efficacy of adaptive transfer of NK and cytotoxic T-lymphocytes mixed effector cells in NSCLC patients.91 A prolonged overall survival was detectable in patients after administration of NK cell-based immunotherapy. In a trial of Lin et al, the clinical outcomes of cryosurgery combined with allogenic NK cell immunotherapy for the treatment of advanced NSCLC were improved with elevated immune functions and quality of life.92

The efficacy of NK cell-based adoptive immunotherapy was also investigated in SCLC patients. Ding et al studied the efficacy and safety of cellular immunotherapy with autologous NK, T cells and cytokine-induced killer cells as maintenance therapy for 29 SCLC patients and demonstrated an increased survival of the patients.93 Importantly, lung cancer-infiltrating NK cells can mainly function as producers of relevant cytokines, either beneficial or detrimental for the antitumor immune response, and activation can transform CD56bright CD162+ KIR2+ NK cells into CD56dim CD161+ KIR1+ NK cells with higher cytotoxic activity.94 The switch from a CD56bright phenotype to a CD56dim NK cell signature can take place in lymph nodes during inflammation and these cells circulate into peripheral blood as KIR+CD16+ NK cells with low cytotoxic ability. However, the secondary lymphoid organ (SLO) NK cells acquire cytotoxic activity upon stimulation with IL-2. Malignant NSCLC tumor areas show high presence of Tregs and minor NK cell infiltration, whereas non-malignant regions were oppositely populated, containing NK cells with marked cytotoxicity ex vivo.95 IL-2 activation of PMBCs exhibit increased cytotoxic activity against primary lung cancer cells, that is further elevated by IL-12 treatment.96 The adoptive transfer of NK cells is a therapeutic strategy currently being investigated in various cancer types. For example, Krause et al treated a NSCLC patient and 11 colorectal cancer patients with autologous transfer of NK cells activated ex vivo by a peptide derived from heat shock protein 70 (Hsp70) plus low-dose IL-2.97 The NK cell reinfusion revealed minor adverse effects and yielded promising immunological alterations.

Adaptive-like CD56dim CD16+ NK cells that were found in studies in mice and humans in peripheral blood have a distinctive phenotypic and functional profile compared to conventional NK cells.31,98 These cells have a high target cell responsiveness, as well as a longer life time and a recall potential comparable to that of memory T cells.99 Whereas adoptive NK cell transfer showed promising activities in the treatment of hematological malignancies, elimination of solid tumor cells failed due to insufficient migration and tumor infiltration.100 Furthermore, a CD49a+ KIR+ NKG2C+ CD56bright CD16 adaptive NK cell population with features of residency exists in human lung, that is distinct from adaptive-like CD56dim CD16+ peripheral blood NK cells.43 NK cells with an adaptive-like CD49a+ NK cell expansion in the lung proved to be hyperresponsive toward cancer cells. Despite their in vivo priming, the presence of adaptive-like CD49a+ NK cells in the lung did not correlate with any clinical parameters.

At the time of diagnosis, the majority (80%) of lung cancer patients present with locally advanced or metastatic disease that continues to progress despite chemotherapy.101 Lung cancer remains the leading cause of cancer death worldwide despite the responses found for immune checkpoint inhibitors (ICIs), including programmed death receptor-1 (PD1) or PD ligand 1 (PDL1)-blockade therapy.102 These ICIs has achieved marked tumor regression in some patients with advanced PD1/PDL1-positive lung cancer; however, lasting responses were limited to a 15% subpopulation of patients.103 IFN-, released by cytotoxic NK and T cells, is a critical enhancer of PDL1 expression on tumors and a predictor of response to immunotherapies.104 The high failure rate of immunotherapy seems to be a consequence of low tumor PDL1 expression and the action of further immunosuppressive mechanisms in the TME.105

NK cells expanded from induced-pluripotent stem cells (iPSCs) increased PDL1 expression of tumor cell lines, sensitized non-responding tumors from patients with lung cancer to PD1-targeted immunotherapy and killed PDL1- patient tumors (Figure 2).102 In contrast, native NK cells, that are susceptible to immunosuppression in the TME, had no effect on tumor PDL1 expression. Accordingly, only combined treatment of expanded NK cells and PD1-directed inhibitors resulted in synergistic tumor cell kill of initially non-responding patient tumors. A randomized control trial in patients with PDL1+ NSCLC found that the combination treatment of NK cells with the PD1 inhibitor pembrolizumab was well-tolerated and improved overall and progression-free survival in patients compared single agent pembrolizumab treatment.106 Importantly, during this clinical study no adverse events associated with the administration of NK cells were detected.

Early trials of autologous NK cell therapy from leukapheresis have demonstrated potency against several metastatic cancers but patients developed vascular leak syndrome due to a high level of IL-2.32,107 In contrast, other studies reported that these autologous NK cells failed to demonstrate clinical responses or efficacy at large.108,109 Adoptive transfer of ex vivo IL-2 activated NK cells showing better outcomes than the systemic administration of IL-2.107,110 The development of novel NK cell-mediated immunotherapies presumes a rich source of suitable NK cells for adoptive transfer and an enhancement of the NK cell cytotoxicity and durability in vivo. Potential sources comprise haploidentical NK cells, umbilical cord blood NK cells, stem cell-derived NK cells, permanent NK cell lines, adaptive NK cells, cytokine-induced memory-like NK cells and chimeric antigen receptor (CAR) NK cells (Figure 2). Augmentation of the cytotoxicity and persistence of NK cells under clinical investigation is promoted by cytokine-based agents, NK cell engager molecules and ICIs.111,112 Despite some successes, most patients failed to respond to unmodified NK cell-based immunotherapy.113

Clonal NK cell lines, such as NK-92, KHYG-1 and YT cells, are an alternative source of allogeneic NK cells, and the NK-92 cell line has been extensively tested in clinical trials.114116 NK-92 cells are easily expanded with doubling times between 24 and 36 hours.115 NK-92 has received FDA approval for trials in patients with solid tumors.116 These cells are genetically unstable, which requires them to be irradiated prior to infusion. Irradiated NK-92 cells have been observed to kill tumor cells in patients with cancer, although irradiation limits the in vivo persistence of these cells to a maximum of 48 hours.117 The results are still short of a significant clinical benefit.118 An NK-92- derived product (haNK) has been engineered to express a high-affinity variant of CD16 as well as endogenous IL-2 in order to enhance effector function (Figure 2).119121 For example, Dinutuximab is a product of human-mouse chimeric mAb (ch14.18 mAb), which has demonstrated high efficacy against GD2-positive neuroblastoma cells in vitro and melanoma cells in vivo.122 In MHC-I expressing tumor cells, the effector functions of autologous NK cells are often inhibited by KIR that can be blocked with the help of anti-KIR (IPH2101).123 Stem cell-derived NK cell products from multiple sources are currently being tested clinically, including those originating from umbilical cord blood stem cells or iPSCs.124,125 NK cells account for ~515% of all lymphocytes in peripheral blood, whereas they constitute up to 30% of the lymphocytes in umbilical cord blood.126 iPSC-derived NK cells were triple gene- modified to express cleavage-resistant CD16, a chimeric antigen receptor (CAR) targeting CD19 and a membrane-bound IL-15 receptor signaling complex in order to promote their persistence.127 Thus, investigations to provide highly active modified NK cells in numbers sufficient for clinical application are actively pursued.

CAR T cells are derived from autologous T cells and genetically engineered to express an antibody single-chain variable fragment (scFv) targeting a tumor-associated antigen.128 CAR T cell therapies achieved objective response rates of >80% in patients with acute lymphocytic leukemia (ALL) and B cell non-Hodgkin lymphoma.129131 However, the drawbacks of CAR T therapy include severe adverse events such as GvHD,cytokine-release syndrome and neurological toxicities, besides inefficiencies of T cell isolation, modification and expansion as well as exorbitant costs.132 CAR NK therapy is expected to circumvent some of these problems, including the high toxicities. Primary NK cells are not ideal sources for the generation of CAR cell products, due to difficulties in cell isolation, transduction and expansion. However, NK cell expansion could be greatly improved by involvement of a K562 leukemia cell line feeder modified to express membrane-bound IL-15 (mbIL-15; Figure 2).133 Denman et al improved this method adding membrane-bound 41BBL to the K562 cell line resulting in a high expansion of NK cells within a short time.134,135 Nevertheless, current clinical trials of CAR NK cells rely mainly on processing of stem cell-derived or progenitor NK cells.136 Genetic engineering of NK cells has been performed by viral transduction or electroporation of mRNA.3 Many clinical trials of CAR NK-92 cells are ongoing, but the requirement for irradiation and resulting short persistence are limitations to the clinical efficacy of these products. NK92-CD16 cells preferentially killed tyrosine kinase inhibitor (TKI)-resistant NSCLC cells when compared with their parental NSCLC cells.137 Moreover, NK92-CD16 cell-induced cytotoxicity against TKI-resistant NSCLC cells was increased in the presence of cetuximab, an EGFR-targeting monoclonal antibody. A number of Phase I trials of CAR NK cells from various sources, including autologous peripheral blood NK cells, umbilical cord blood NK cells, NK-92 cells and iPSCs were designed to target diverse cancers, such as ALL, B cell malignancies, NSCLC, ovarian cancer or glioblastoma, and are currently active.

CAR NK cells derived from iPSCs, such as the triple-gene-modified constructions are described as a promising alternative. For example, a tri-specific killer engager (TriKE) consists of two scFvs, one targeting CD16 on NK cells and the other targeting CD33 on AML cells, linked by an IL-15 domain that promotes NK cell survival and proliferation.138 Controlled clinical trials with larger patient cohorts are required to validate these early results. Immunosuppressive factors of the TME, such as low glucose, hypoxia and MDSCs, Treg cells and tumor associated macrophages (TAMs) still suppress the antitumor functions of CAR-NK cells. Low efficiency of CAR-transduction, limited cell expansion and the scarcity of suitable targets impede the use of CAR-NK therapy despite of reports of therapeutic efficacy and safety.139

The cytokine gene transfer approaches, including interleukins and stem cell factor (SCF), have been shown to induce NK cell proliferation and increases survival capacity in vivo.140 The use of primary CAR-NK and CAR-NK lines in hematological tumors showed high specificity and cytotoxicity toward the target cells.141,142 So far, only a few clinical trial studies of CAR-NK have been registered on The combination of blocking ICIs on CAR-NK cells can lead to a highly efficient cancer-redirected cytotoxic activity.144,145 However, hematological cancers are responsible for only 6% of all cancer deaths and solid tumor are much more difficult to target by NK/CAR NK-based immunotherapy.146

Both the unmodified and the engineered forms of NK cell treatment are showing promise in pilot clinical trials in patients with cancer.147 This kind of immunotherapy seems to combine efficacy, safety, and relative ease of effector cell supply. The lung is populated by NK cells at a specific differentiation stage releasing cytokines but exhibiting low cytotoxicity. Poor tumor infiltration, immunosuppressive factors and cell types as well as hypoxic conditions in the TME limit the activity of NK cells. Therefore, larger numbers of activated, cytotoxic competent and armed NK cells will be required for successful therapy.

We wish to thank B. Rath for help in the preparation of the manuscript and T. Hohenheim for enduring endorsement.

The authors report no conflicts of interest in this work.

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67. Zhu M, Huang Y, Bender ME, et al. Evasion of innate immunity contributes to small cell lung cancer progression and metastasis. Cancer Res. 2021;81(7):18131826. doi:10.1158/0008-5472.can-20-2808

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Beyond CAR-T: New Frontiers in Living Cell Therapies – UCSF News Services

By daniellenierenberg

Our cells have abilities that go far beyond the fastest, smartest computer. They generate mechanical forces to propel themselves around the body and sense their local surroundings through a myriad of channels, constantly recalibrating their actions.

The idea of using cells as medicine emerged with bone marrow transplants, and then CAR-T therapy for blood cancers. Now, scientists are beginning to engineer much more complex living therapeutics by tapping into the innate capabilities of living cells to treat a growing list of diseases.

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That includes solid tumors like cancers of the brain, breast, lung, or prostate, and also inflammatory diseases like diabetes, Crohns, and multiple sclerosis. One day, this work may extend to regenerating tissues outside or even inside the body.

Taking a page from computer engineers, biologists are trying their hands at programming cells by building DNA circuits to guide their protein-making machinery and behavior.

We need cells with GPS that never make mistakes in where they need to go, and with sensors that give them real-time information before they deliver their payload, said Hana El-Samad, PhD, a professor of biochemistry and biophysics. Maybe they kill a little bit and then deliver a therapeutic payload that cleans up. And the next program over encourages the rejuvenation of healthy cells.

These engineered cell therapies would be a huge leap from traditional therapies, like small molecules and biologics, which can only be controlled through dose, or combination, or by knowing the time it takes for the body to get rid of it.

If you put in drugs, you can block things and push things one way or the other, but you can't read and monitor whats going on, said Wendell Lim, PhD, a professor of cellular and molecular pharmacology who directs the Cell Design Institute at UCSF. A living cell can get into the disease ecosystem and sense what's going on, and then actually try to restore that ecosystem.

Like people, cells live in communities and share duties. They even take on new identities when the need arises, operating through unseen forces that biologists term, self-organizing.

We need cells with GPS that never make mistakes in where they need to go, and with sensors that give them real-time information before they deliver their payload.

Hana El-Samad, PhD

Some living cell therapies could be controlled even after they enter the body.

Lim and others say it is possible to begin adapting cells into therapy, even when so much has yet to be learned about human biology, because cells already know so much.

Their built-in power includes dormant embryonic abilities, so a genetic nudge in the right place could enable a cell to assume a new function, even something it has never done before.

When a cell, a building block thats 10 microns in diameter can do that, and you have 10 trillion of them in your body, its a whole new ballgame, said Zev Gartner, PhD, a professor of pharmaceutical chemistry who studies how tissues form. Were not talking about engineering in the same way that somebody working at Ford or Intel or Apple or anywhere else thinks about engineering. Its a whole new way of thinking about engineering and construction.

For several years now, synthetic biologists have been building rudimentary feedback circuits in model organisms like yeast by inserting engineered DNA programs. Recently, Lim and El-Samad put these circuits into mice to see if they could tamp down the excess inflammation from traumatic brain injury.

They demonstrated that engineered T-cells could get into the sites of injury in the brain and perform an immune-modulating function. But its just a prototype of what synthetic circuits could do.

You can imagine all kinds of scenarios of therapies that dont cause any side effects, and do not have any collateral damage, said El-Samad.

UCSF researchers are building ever more complex circuits to move cells around the body and sense their surroundings. They hope to load them with DNA programs that trigger the cells protein-making machinery to do things like remove cancerous cells, then repair the damage caused by the tumors haphazard growth.

Or they could make cells that send signals to finetune the immune system when it overreacts to a threat or mistakenly attacks healthy cells. Or build new tissue and organs from our bodys own cells to repair damage associated with trauma, disease, or aging.

The fact that biological systems and cellular systems can self-organize is a huge part of biology, and thats something were starting to program, Lim said. Then we can make cells that do the functions that we want. We aspire to not only have immune cells be better at killing and detecting cancer but also to suppress the immune system for autoimmunity and inflammation or go to the brain to fight degeneration.

These UCSF scientists are on their way to engineering cell-based solutions to different diseases.

Tejal Desai, PhD, a professor and chair of the Department of Bioengineering and Therapeutic Sciences, is employing nanotechnology to create tiny depots where cells that have been engineered to treat Type 1 diabetes or cancer can refuel with oxygen and nutrients.

Having growth factors or other factors that keep them chugging along is very helpful, she said. Certain cytokines help specific immune cells proliferate in the body. We can design synthetic particles that present cytokines and have a signal that says, Come over to me. Basically, a homing signal.

Ophir Klein, MD, PhD, a professor of orofacial sciences and pediatrics, employs stem cell biology to research treatments for birth defects and conditions like inflammatory bowel disease. He is working with Lim and Gartner to create circuits that induce cells to grow in new ways, for example to repair the damage to intestines in Crohns disease.

Cells and tissues are able to do things that historically we thought they were incapable of doing, Klein said. We dont assume that the way things happen or dont happen is the best way that they can happen, and were trying to figure out if there are even better ways.

Faranak Fattahi, PhD, a Sandler Faculty Fellow, is developing cell replacement therapy for damaged or missing enteric neurons, which regulate the muscles that move food through the GI tract. She generated these gut neurons using iPS cell technology.

What we want to do in the lab is see if we can figure out how these nerves are misbehaving and reverse it before transplanting them inside the tissue, she said. Now, she is working with Lim to refine the cells, so they integrate into tissues more efficiently without being killed off by the immune system and work better in reversing the disease.

Matthias Hebrok, PhD, a professor in the Diabetes Center, has created pancreatic islets, a complex cellular ecosystem containing insulin-producing beta cells, glucagon-producing alpha cells and delta cells.

Now, he is working on how to make islet transplants that dont trigger the immune system, so diabetes patients can receive them without immune-suppressing drugs.

We might be able to generate stem-cell derived organs that the recipients immune system will either recognize as self or not react to in a way that would disrupt their function.

In health, the community of cells in these islets perform the everyday miracle of keeping your blood sugar on an even keel, regardless of what you ate or drank, or how little or how much you exercised or slept.

To me, at least, thats the most remarkable thing about our cells, Gartner said. All of this stuff just happens on its own.

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Gamida Cell Announces Publication in Blood, the Journal of the American Society of Hematology, of the First Pivotal Trial to Evaluate a Cell Therapy…

By daniellenierenberg

BOSTON--(BUSINESS WIRE)--Gamida Cell Ltd. (Nasdaq: GMDA), an advanced cell therapy company committed to cures for blood cancers and serious hematologic diseases, today announced that the results of a Phase 3 clinical study of omidubicel have been published in Blood, the official journal of the American Society of Hematology. Omidubicel is an advanced cell therapy under development as a potential life-saving allogeneic hematopoietic stem cell transplant solution for patients with hematologic malignancies.

The results demonstrate that transplantation with omidubicel leads to faster neutrophil and platelet recovery compared to a standard umbilical cord blood graft, and results in fewer early bacterial and viral infections and less time in the hospital.

We are pleased that the data from this well-conducted international Phase 3 trial have been published in Blood, the highly respected, peer-reviewed journal of the American Society of Hematology, said Ronit Simantov, M.D., chief medical officer of Gamida Cell. The robust results of this clinical trial have demonstrated that omidubicel could provide an important new option for patients with hematologic malignancies in need of a bone marrow transplant.

Data from this study were previously presented at the Transplantation & Cellular Therapy Meetings of the American Society of Transplantation and Cellular Therapy and Center for International Blood & Marrow Transplant Research, and most recently during the Presidential Symposium at the 47th Annual Meeting of the European Society for Blood and Marrow Transplantation. The pivotal study was an international, multi-center, randomized Phase 3 trial designed to compare the safety and efficacy of omidubicel to standard umbilical cord blood transplant in patients with high-risk hematologic malignancies undergoing a bone marrow transplant.

Previous studies have shown that engraftment with omidubicel is durable, with some patients in the Phase 1/2 study now a decade past their transplant. The Phase 3 data reinforce omidubicels potential to be a new standard of care for patients who are in need of stem cell transplantation but do not have access to an appropriate matched donor, said Mitchell Horwitz, M.D., lead author of the paper and a professor of medicine at the Duke Cancer Institute.

The full Blood manuscript is available here:

Details of Phase 3 Efficacy and Safety Results Shared in Blood

The intent-to-treat analysis included 125 patients aged 1365 years with a median age of 41. Forty-four percent of the patients treated on study were non-Caucasian, a population known to be underrepresented in adult bone marrow donor registries. Patient demographics and baseline characteristics were well-balanced across the two study groups. Patients with acute lymphoblastic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, myelodysplastic syndrome or lymphoma were enrolled at more than 30 clinical centers in the United States, Europe, Asia, and Latin America.

Gamida Cell previously reported in May 2020 that the study achieved its primary endpoint, showing that omidubicel demonstrated a statistically significant reduction in time to neutrophil engraftment, a measure of how quickly the stem cells a patient receives in a transplant are established and begin to make healthy new cells and a key milestone in a patients recovery from a bone marrow transplant. The median time to neutrophil engraftment was 12 days for patients randomized to omidubicel compared to 22 days for the comparator group (p<0.001).

All three secondary endpoints, details of which were first reported in December 2020, demonstrated a statistically significant improvement among patients who were randomized to omidubicel compared to patients randomized to standard cord blood graft. Platelet engraftment was significantly accelerated with omidubicel, with 55 percent of patients randomized to omidubicel achieving platelet engraftment at day 42, compared to 35 percent for the comparator (p = 0.028). Hospitalization in the first 100 days after transplant was also reduced in patients randomized to omidubicel, with a median number of days alive and out of hospital for patients randomized to omidubicel of 61 days, compared to 48 days for the comparator (p=0.005). The rate of infection was significantly reduced for patients randomized to omidubicel, with the cumulative incidence of first grade 2 or grade 3 bacterial or invasive fungal infection for patients randomized to omidubicel of 37 percent, compared to 57 percent for the comparator (p=0.027). Additional data reported in the manuscript included a comparison of infection density, or the number of infections during the first year following transplantation, which showed that the risk for grade 2 and grade 3 infections was significantly lower among recipients of omidubicel compared to control (risk ratio 0.5, p<0.001).

Data from the study relating to exploratory endpoints also support the clinical benefit demonstrated by the studys primary and secondary endpoints. There was no statistically significant difference between the two patient groups in incidence of grade 3/4 acute GvHD (14 percent for omidubicel, 21 percent for the comparator) or all grades chronic GvHD at one year (35 percent for omidubicel, 29 percent for the comparator). Non-relapse mortality was shown to be 11 percent for patients randomized to omidubicel and 24 percent for patients randomized to the comparator (p=0.09).

These clinical data results form the basis of a Biologics License Application (BLA) that Gamida Cell plans to submit to the U.S. Food and Drug Administration (FDA) in the fourth quarter of 2021.

About Omidubicel

Omidubicel is an advanced cell therapy under development as a potential life-saving allogeneic hematopoietic stem cell (bone marrow) transplants for patients with hematologic malignancies (blood cancers), for which it has been granted Breakthrough Status by the FDA. Omidubicel is also being evaluated in a Phase 1/2 clinical study in patients with severe aplastic anemia (NCT03173937). The aplastic anemia investigational new drug application is currently filed with the FDA under the brand name CordIn, which is the same investigational development candidate as omidubicel. For more information on clinical trials of omidubicel, please visit

Omidubicel is an investigational therapy, and its safety and efficacy have not been established by the FDA or any other health authority.

About Gamida Cell

Gamida Cell is an advanced cell therapy company committed to cures for patients with blood cancers and serious blood diseases. We harness our cell expansion platform to create therapies with the potential to redefine standards of care in areas of serious medical need. For additional information, please visit or follow Gamida Cell on LinkedIn or Twitter at @GamidaCellTx.

Cautionary Note Regarding Forward Looking Statements

This press release contains forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995, including with respect to the potential for omidubicel to become a new standard of care and the anticipated submission of a BLA for omidubicel, which statements are subject to a number of risks, uncertainties and assumptions, including, but not limited to Gamida Cells ability to prepare regulatory filings and the review process therefor; complications in Gamida Cells plans to manufacture its products for commercial distribution; and clinical, scientific, regulatory and technical developments. In light of these risks and uncertainties, and other risks and uncertainties that are described in the Risk Factors section and other sections of Gamida Cells Annual Report on Form 20-F, filed with the Securities and Exchange Commission (SEC) on March 9, 2021, as amended on March 22, 2021, and other filings that Gamida Cell makes with the SEC from time to time (which are available at, the events and circumstances discussed in such forward-looking statements may not occur, and Gamida Cells actual results could differ materially and adversely from those anticipated or implied thereby. Any forward-looking statements speak only as of the date of this press release and are based on information available to Gamida Cell as of the date of this release.

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Investing in stem cells, the building blocks of the body – MoneyWeek

By daniellenierenberg

Imagine being able to reverse blindness, cure multiple sclerosis (MS), or rebuild your heart muscles after a heart attack. For the past few decades, research into stem cells, the building blocks of tissues and organs, has raised the prospect of medical advances of this kind yet it has produced relatively few approved treatments. But that could be about to change, says Robin Ali, professor of human molecular genetics of Kings College London. Just as gene therapy went from being a fantasy with little practical value to becoming a major area of treatment, stem cells are within a few years of reaching the medical mainstream. Whats more, developments in synthetic biology, the process of engineering and re-engineering cells, could make stem cells even more effective.

Stem cells are essentially the bodys raw material: basic cells from which all other cells with particular functions are generated. They are found in various organs and tissues, including the brain, blood, bone marrow and skin. The primary promise of adult stem cells lies in regenerative medicine, says Professor Ali.

Stem cells go through several rounds of division in order to produce specialist cells; a blood stem cell can be used to produce blood cells and skin stem cells can be used to produce skin cells. So in theory you can take adult stem cells from one person and transplant them into another person in order to promote the growth of new cells and tissue.

In practice, however, things have proved more complicated, since the number of stem cells in a persons body is relatively limited and they are hard to access. Scientists were also previously restricted by the fact that adult stem cells could only produce one specific type of cell (so blood stem cells couldnt produce skin cells, for instance).

In their quest for a universal stem cell, some scientists initially focused on stem cells from human embryos, but that remains a controversial method, not only because harvesting stem cells involves destroying the embryo, but also because there is a much higher risk of rejection of embryonic stem cells by the recipients immune system.

The good news is that in 2006 Japanese scientist Shinya Yamanaka of Kyoto University and his team discovered a technique for creating what they call induced pluripotent stem cells (iPSC). The research, for which they won a Nobel Prize in 2012, showed that you can rewind adult stem cells development process so that they became embryo-like stem cells. These cells can then be repurposed into any type of stem cells. So you could turn skin stem cells into iPSCs, which could in turn be turned into blood stem cells.

This major breakthrough has two main benefits. Firstly, because iPSCs are derived from adults, they dont come with the ethical problems associated with embryonic stem cells. Whats more, the risk of the body rejecting the cells is much lower as they come from another adult or are produced by the patient. In recent years scientists have refined this technique to the extent that we now have a recipe for making all types of cells, as well as a growing ability to multiply the number of stem cells, says Professor Ali.

Having the blueprint for manufacturing stem cells isnt quite enough on its own and several barriers remain, admits Professor Ali. For example, we still need to be able to manufacture large numbers of stem cells at a reasonable cost. Ensuring that the stem cells, once they are in the recipient, carry out their function of making new cells and tissue remains a work in progress. Finally, regulators are currently taking a hard line towards the technology, insisting on exhaustive testing and slowing research down.

The good news, Professor Ali believes, is that all these problems are not insurmountable as scientists get better at re-engineering adult cells (a process known as synthetic biology). The costs of manufacturing large numbers of stem cells are falling and this can only speed up as more companies invest in the area. There are also a finite number of different human antigens (the parts of the immune system that lead a body to reject a cell), so it should be possible to produce a bank of iPSC cells for the most popular antigen types.

While the attitude of regulators is harder to predict, Professor Ali is confident that it needs only one major breakthrough for the entire sector to secure a large amount of research from the top drug and biotech firms. Indeed, he believes that effective applications are likely in the next few years in areas where there are already established transplant procedures, such as blood transfusion, cartilage and corneas. The breakthrough may come in ophthalmology (the treatment of eye disorders) as you only need to stimulate the development of a relatively small number of cells to restore someones eyesight.

In addition to helping the body repair its own tissues and organs by creating new cells, adult stem cells can also indirectly aid regeneration by delivering other molecules and proteins to parts of the body where they are needed, says Ralph Kern, president and chief medical officer of biotechnology company BrainStorm Cell Therapeutics.

For example, BrainStorm has developed NurOwn, a cellular technology using peoples own cells to deliver neurotrophic factors (NTFs), proteins that can promote the repair of tissue in the nervous system. NurOwn works by modifying so-called Mesenchymal stem cells (MSCs) from a persons bone marrow. The re-transplanted mesenchymal stem cells can then deliver higher quantities of NTFs and other repair molecules.

At present BrainStorm is using its stem-cell therapy to focus on diseases of the brain and nervous system, such as amyotrophic lateral sclerosis (ALS, also known as Lou Gehrigs disease), MS and Huntingtons disease. The data from a recent final-stage trial suggests that the treatment may be able to halt the progression of ALS in those who have the early stage of the disease. Phase-two trial (the second of three stages of clinical trials) of the technique in MS patients also showed that those who underwent the treatment experienced an improvement in the functioning of their body.

Kern notes that MSCs are a particularly promising area of research. They are considered relatively safe, with few side effects, and can be frozen, which improves efficiency and drastically cuts down the amount of bone marrow that needs to be extracted from each patient.

Because the manufacture of MSC cells has become so efficient, NurOwn can be used to get years of therapy in one blood draw. Whats more, the cells can be reintroduced into patients bodies via a simple lumbar puncture into the spine, which can be done as an outpatient procedure, with no need for an overnight stay in hospital.

Kern emphasises that the rapid progress in our ability to modify cells is opening up new opportunities for using stem cells as a molecular delivery platform. Through taking advantage of the latest advances in the science of cellular therapies, BrainStorm is developing a technique to vary the molecules that its stem cells deliver so they can be more closely targeted to the particular condition being treated. BrainStorm is also trying to use smaller fragments of the modified cells, known as exosomes, in the hope that these can be more easily delivered and absorbed by the body and further improve its ability to avoid immune-system reactions to unrelated donors. One of BrainStorms most interesting projects is to use exosomes to repair the long-term lung damage from Covid-19, a particular problem for those with long Covid-19. Early preclinical trials show that modified exosomes delivered into the lungs of animals led to remarkable improvements in their condition. This included increasing the lungs oxygen capacity, reducing inflammation, and decreasing clotting.

Overall, while Kern admits that you cant say that stem cells are a cure for every condition, there is a lot of evidence that in many specific cases they have the potential to be the best option, with fewer side effects. With Americas Food and Drug Administration recently deciding to approve Biogens Alzheimers drug, Kern thinks that they have become much more open to approving products in diseases that are currently considered untreatable. As a result, he thinks that a significant number of adult stem-cell treatments will be approved within the next five to ten years.

Adult stem cells and synthetic biology arent just useful in treatments, says Dr Mark Kotter, CEO and founder of Bit Bio, a company spun out of Cambridge University. They are also set to revolutionise drug discovery. At present, companies start out by testing large numbers of different drug combinations in animals, before finding one that seems to be most effective. They then start a process of clinical trials with humans to test whether the drug is safe, followed by an analysis to see whether it has any effects.

Not only is this process extremely lengthy, but it is also inefficient, because human and animal biology, while similar in many respects, can differ greatly for many conditions. Many drugs that seem promising in animals end up being rejected when they are used on humans. This leads to a high failure rate. Indeed, when you take the failures into account, it has been estimated that it may cost as much to around $2bn to develop the typical drug.

As a result, pharma companies are now realising that you have to insert the human element at a pre-clinical stage by at least using human tissues, says Kotter. The problem is that until recently such tissues were scarce, since they were only available from biopsies or surgery. However, by using synthetic biology to transform adult stem cells from the skin or other parts of the body into other types of stem cells, researchers can potentially grow their own cells, or even whole tissues, in the laboratory, allowing them to integrate the human element at a much earlier stage.

Kotter has direct experience of this himself. He originally spent several decades studying the brain. However, because he had to rely on animal tissue for much of his research he became frustrated that he was turning into a rat doctor.

And when it came to the brain, the differences between human and rat biology were particularly stark. In fact, some human conditions, such as Alzheimers, dont even naturally appear in rodents, so researchers typically use mice and rats engineered to develop something that looks like Alzheimers. But even this isnt a completely accurate representation of what happens in humans.

As a result of his frustration, Kotter sought a way to create human tissues. It initially took six months. However, his company, Bit Bio, managed to cut costs and greatly accelerate the process. The companys technology now allows it to grow tissues in the laboratory in a matter of days, on an industrial scale. Whats more, the tissues can also be designed not just for particular conditions, such as dementia and Huntingdons disease, but also for particular sub-types of diseases.

Kotter and Bit Bio are currently working with Charles River Laboratories, a global company that has been involved in around 80% of drugs approved by the US Food and Drug Administration over the last three years, to commercialise this product. They have already attracted interest from some of the ten largest drug companies in the world, who believe that it will not only reduce the chances of failure, but also speed up development. Early estimates suggest that the process could double the chance of a successful trial, effectively cutting the cost of each approved drug by around 50% from $2bn to just $1bn. This in turn could increase the number of successful drugs on the market.

Two years ago my colleague Dr Mike Tubbs tipped Fate Therapeutics (Nasdaq: FATE). Since then, the share price has soared by 280%, thanks to growing interest from other drug companies (such as Janssen Biotech and ONO Pharmaceutical) in its cancer treatments involving genetically modified iPSCs.

Fate has no fewer than seven iPSC-derived treatments undergoing trials, with several more in the pre-clinical stage. While it is still losing money, it has over $790m cash on hand, which should be more than enough to support it while it develops its drugs.

As mentioned in the main story, the American-Israeli biotechnology company BrainStorm Cell Therapeutics (Nasdaq: BCLI) is developing treatments that aim to use stem cells as a delivery mechanism for proteins. While the phase-three trial (the final stage of clinical trials) of its proprietary NurOwn system for treatment of Amyotrophic lateral sclerosis (ALS, or Lou Gehrigs disease) did not fully succeed, promising results for those in the early stages of the disease mean that the company is thinking about running a new trial aimed at those patients. It also has an ongoing phase-two trial for those with MS, a phase-one trial in Alzheimers patients, as well as various preclinical programmes aimed at Parkinsons, Huntingtons, autistic spectrum disorder and peripheral nerve injury. Like Fate Therapeutics, BrainStorm is currently unprofitable.

Australian biotechnology company Mesoblast (Nasdaq: MESO) takes mesenchymal stem cells from the patient and modifies them so that they can absorb proteins that promote tissue repair and regeneration. At present Mesoblast is working with larger drug and biotech companies, including Novartis, to develop this technique for conditions ranging from heart disease to Covid-19. Several of these projects are close to being completed.

While the US Food and Drug Administration (FDA) controversially rejected Mesoblasts treatment remestemcel-L for use in children who have suffered from reactions to bone-marrow transplants against the advice of the Food and Drug Administrations own advisory committee the firm is confident that the FDA will eventually change its mind.

One stem-cell company that has already reached profitability is Vericel (Nasdaq: VCEL). Vericels flagship MACI products use adult stem cells taken from the patient to grow replacement cartilage, which can then be re-transplanted into the patient, speeding up their recovery from knee injuries. It has also developed a skin replacement based on skin stem cells.

While earnings remain relatively small, Vericel expects profitability to soar fivefold over the next year alone as the company starts to benefit from economies of scale and runs further trials to expand the range of patients who can benefit.

British micro-cap biotech ReNeuron (Aim: RENE) is developing adult stem-cell treatments for several conditions. It is currently carrying out clinical trials for patients with retinal degeneration and those recovering from the effects of having a stroke. ReNeuron has also developed its own induced pluripotent stem cell (iPSC) platform for research purposes and is seeking collaborations with other drug and biotech companies.

Like other small biotech firms in this area, it is not making any money, so it is an extremely risky investment although the rewards could be huge if any of its treatments show positive results from their clinical trials.

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Sickle Cell Plagues Many Black Americans, But There’s Hope for Better Treatments – HealthDay News

By daniellenierenberg

FRIDAY, June 18, 2021 (HealthDay News) -- It's been more than six months since Brandy Compton last landed in a hospital emergency room.

That's an amazing medical achievement, brought about by scientific breakthroughs that have been unfortunately overshadowed by the coronavirus pandemic, experts say.

Compton, 31, was born with sickle cell disease, a genetic condition that primarily affects people of African descent.

The disease causes episodes of pain so bad that in the past, Compton had to be hospitalized frequently for full blood transfusions.

"In grade school, I was in the hospital for a week, I'd get out of the hospital for maybe a good week and a half, two weeks, and then I'd be back in the hospital for another week," recalls Compton, who lives in Hartford, Conn. "It was constant."

But last year Compton started on a once-monthly IV drug called Adakveo (crizanlizumab), one of a handful of new sickle cell drugs approved by the U.S. Food and Drug Administration just before the pandemic hit.

The drug has cut in half the amount of blood Compton requires during a transfusion, and has prevented the sort of pain crisis that would send her to an ER, she said.

As the pandemic subsides, sickle cell disease experts are now trying to spread the word about these handful of treatments that could improve and potentially extend the lives of patients.

"In the last three years or so, three new medicines got approved by the FDA with different ways of working that could actually be used together and give more preventive, disease-modifying types of approaches rather than just waiting for the bad complications to occur," said Dr. Lewis Hsu, chief medical officer of the Sickle Cell Disease Association of America.

Progress also is being made on cures that would fix the genetic error that causes sickle cell, either through a donor bone marrow transplant or gene therapy that would fix the patient's own stem cells, Hsu added.

'Jagged rocks shredding your veins'

Sickle cell disease affects the shape of a person's red blood cells, which are normally disc-shaped and flexible enough to move easily through blood vessels.

The red blood cells of a person with sickle cell are crescent-shaped, resembling a sickle. The cells are stiff and sticky, and cause pain episodes and other health problems when they clump together in different parts of the body. They also are less capable of carrying oxygen to a person's tissues, causing chronic fatigue.

"Sickle cell feels like jagged rocks shredding the inside of your veins, and your bones being crushed," Compton says.

Sickle cell disproportionately affects Black people in the United States. About 1 in 13 Black babies is born with the genetic trait for sickle cell, and about 1 in every 365 Black babies is born with sickle cell disease, according to the U.S. National Institutes of Health.

For a long time, there was no treatment at all for sickle cell, Hsu said, outside of regular blood transfusions.

"At the age of 13, I started getting blood transfusions," Compton recalls. "After that, it started getting under control. I would be able to go about a month without having to be hospitalized. That time got longer as I got older."

In 1998, the FDA approved hydroxyurea, an oral medicine that can reduce or prevent sickle cell complications in people with specific subtypes of the disease. But following that, there was a "long gap" in new treatments, Hsu said.

That ended in 2017 with the approval of L-glutamine powder, sold under the brand name Endari. Patients sprinkle a packet of this purified amino acid powder on their food or drink twice a day, Hsu said.

"Particularly, it help the red cells be healthier and have better energy stores," Hsu said.

But the two real breakthroughs occurred in November 2019, on the cusp of the pandemic, with FDA approval of two new drugs -- Adaveko and Oxbryta (voxelotor).

Adaveko essentially creates an "oil slick" in the bloodstream that keeps sickled red blood cells from clumping, explained Genice Nelson, program director of the New England Sickle Cell Institute at the University of Connecticut. She also leads Compton's care.

"It helps to improve blood flow by having the cells move along better, gliding instead of sticking to each other," Hsu said.

Showing promise at a high price

Thanks to Adaveko, Compton now only needs four units of blood every four weeks, down from seven, and does not suffer frequent pain episodes.

The other drug, Oxbryta, improves the ability of deformed red blood cells to hold onto oxygen, Nelson said.

"It inhibits the deformation of the red blood cell, so it's able to hold onto oxygen," Nelson said. "Because the red blood cell is able to hold onto oxygen, it's able to give that oxygen to the tissues within the body."

Because these drugs act in different ways, the hope is that a sickle cell patient taking two or more would receive added benefits, Hsu said.

Unfortunately, the new drugs are expensive and insurance companies have balked at paying for them, Hsu said.

For example, Adakveo costs about $10,000 a month for a patient, Nelson said. It seems like a great expense, but is likely cheaper than regular ER visits.

"If someone is in the hospital several days out of the month every month, dollar for dollar you'd rather invest it in preventing them from being in the hospital rather than trying to treat them once they're in the hospital," Nelson said.

Despite this, insurance companies have dragged their feet accepting the new drugs.

"We have great, great difficulty prescribing them and getting them authorized," Hsu said. "It's a case-by-case issue for every single prescription. It takes two months or so to get the authorizations, and then we go for refills or another prescription and they have to go through the same process again."

Experts hope that the track record of these drugs will lead insurance companies to relent.

"The data is clear there is benefit to patients being on disease-modifying therapies," said Dr. Alexis Thompson, head of hematology for the Ann & Robert Lurie Children's Hospital in Chicago. "The natural history of sickle cell disease is devastating. To not think about where the opportunities are to intervene early, to modify the natural history of the disease and really reduce suffering, is something we all need to be committed to."

Great progress also has been made in cures for sickle cell, Hsu added.

Transplants tricky, but improvements underway

For a long time, the only potential cure was a full bone marrow transplant from a genetically matched donor, usually a sibling, Hsu said. Only children could handle the stress of this cure, because their existing bone marrow had to be killed off through chemotherapy prior to the transplant.

But improved medications that inhibit immune system rejection now have made transplants also available to children who have a half-matched relative. These drugs selectively inhibit immune attack cells without harming the healthy stem cells being transplanted, Hsu said.

Over the past decade, even adult sickle cell patients have been receiving transplants, through a method that replaces most but not all of the person's bone marrow.

"This is a mixture that's enough to allow the donor to supply most of the red cells that are floating around, so they're not sickle red cells, and the tiny portion of host red cells are diluted heavily," Hsu said. "This has found to be successful and stable."

Five to seven research groups also are working on what could be the ultimate cure for sickle cell, a gene therapy that would take the person's own bone marrow and fix it to remove the genetic anomaly that causes the disease.

"You'd no longer have to find a donor for the stem cells," Hsu said. "You basically do your own donation of stem cells."

Research efforts are focused on fixing the stem cells by treating them with a genetically modified virus, or by using newly discovered methods of gene editing, Hsu said. In both cases, the person's bone marrow is removed, treated in a lab, and then put back inside them.

These efforts have met with some hurdles, with the gene therapy causing leukemia in something like 2 of every 47 cases in some instances, Hsu said.

"We do need to keep working on ways to limit the side effects or toxicity of those approaches, but one cannot argue that the early data is quite remarkable," Thompson said.

Compton, now the mother of a healthy 9-year-old boy, is hopeful that these efforts will lead to a cure, even though she doesn't expect to benefit from one at her age.

"I know about gene therapy and things like that," Compton said. "I do hope there would be a cure available."

More information

The Mayo Clinic has more about sickle cell disease.

SOURCES: Brandy Compton, Hartford, Conn.; Lewis Hsu, MD, PhD, chief medical officer, Sickle Cell Disease Association of America; Alexis Thompson, MD, MPH, head, hematology, Ann & Robert Lurie Children's Hospital, Chicago; Genice Nelson, DNP, program director, New England Sickle Cell Institute, University of Connecticut, Farmington

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Sickle Cell Plagues Many Black Americans, But There's Hope for Better Treatments - HealthDay News

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Jasper Therapeutics and Aruvant Announce Research Collaboration to Study JSP191, an Antibody-Based Conditioning Agent, with ARU-1801, a Novel Gene…

By daniellenierenberg

REDWOOD CITY, Calif. and NEW YORK and BASEL, Switzerland, June 21, 2021 /PRNewswire/ --Jasper Therapeutics, Inc., a biotechnology company focused on hematopoietic cell transplant therapies, andAruvant Sciences, a private company focused on developing gene therapies for rare diseases, today announced that they have entered a non-exclusive research collaboration to evaluate the use of JSP191, Jasper's anti-CD117 monoclonal antibody, as a targeted, non-toxic conditioning agent with ARU-1801, Aruvant's investigational lentiviral gene therapy for sickle cell disease (SCD). The objective of the collaboration is to evaluate the use of JSP191 as an effective and more tolerable conditioning agent that can expand the number of patients who can receive ARU-1801, a potentially curative treatment for SCD.

"This research collaboration with Aruvant is the first to use a clinical-stage antibody-based conditioning agent and a novel clinical-stage gene therapy, giving this combination a clear advantage by moving beyond the harsh conditioning agents currently used for gene therapy and establishing this next-generation potentially curative treatment as a leader in sickle cell disease," said Kevin N. Heller, M.D., executive vice president, research and development of Jasper. "Our goal is to establish JSP191 as a potential new standard of care conditioning agent, broadly in autologous gene therapy and allogeneic hematopoietic stem cell transplantation."

Gene therapies and gene editing technologies generally require that a patient's own hematopoietic stem cells first be depleted from the bone marrow to facilitate the engraftment of the new, gene-modified stem cells through a process called conditioning. Other investigational gene therapies and gene editing approaches in SCD use a high-dose chemotherapy such as busulfan for the conditioning regimen, which can place patients at prolonged risk for infection and bleeding, secondary malignancy and infertility. ARU-1801 is currently the only gene therapy that has demonstrated durable efficacy using both a lower dose of chemotherapy and a different agent than busulfan with a more limited side effect profile. The Aruvant-Jasper partnership is focused on evaluating the potential of using JSP191, a highly targeted anti-CD117 (stem cell factor receptor) monoclonal antibody agent, as the foundationof a novel conditioning regimen for use in combination with ARU-1801 to further reduce the negative side effects while maintaining efficacy.

"The unique attributes of ARU-1801 enable us to bring a potentially curative one-time therapy to individuals with sickle cell disease that can be delivered in the safest way possible," said Will Chou, M.D., Aruvant chief executive officer. "By partnering with Jasper to evaluate the use of JSP191 with ARU-1801, we are one step closer to developing a next-generation definitive therapy with an even more patient-friendly conditioning regimen. We believe that this combination may be able to further expand the number of patients who can benefit from ARU-1801 in the future, including potentially those with more moderate disease."

About JSP191 JSP191 is a humanized monoclonal antibody in clinical development as a conditioning agent that blocks stem cell factor receptor signaling leading to clearance of hematopoietic stem cells from bone marrow, creating an empty space for donor or gene-corrected transplanted stem cells to engraft. While hematopoietic cell transplantation can be curative for patients, its use is limited because standard high dose myeloablative conditioning is associated with severe toxicities and standard low dose conditioning has limited efficacy. To date, JSP191 has been evaluated in more than 90 healthy volunteers and patients. It is currently enrolling in two clinical trials for myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) and severe combined immunodeficiency (SCID) and expects to begin enrollment in four additional studies in 2021 for severe autoimmune disease, sickle cell disease, chronic granulomatous disease and Fanconi anemia patients undergoing hematopoietic cell transplantation.

About ARU-1801 ARU-1801 is designed to address the limitations of current curative treatment options, such as low donor availability and the risk of graft-versus-host disease (GvHD) seen with allogeneic stem cell transplants. Unlike investigational gene therapies and gene editing approaches which require fully myeloablative conditioning, the unique characteristics of ARU-1801 allow it to be given with reduced intensity conditioning ("RIC"). Compared to myeloablative approaches, the lower dose chemotherapy regimen underlying RIC has the potential to reduce not only hospital length of stay, but also the risk of short- and long-term adverse events such as infection and infertility. Preliminary clinical data from the MOMENTUMstudy, an ongoing Phase 1/2 trial of ARU-1801 in patients with severe sickle cell disease, demonstrate continuing durable reductions in disease burden.

The MOMENTUM Study Aruvant is conducting the MOMENTUM study, which is evaluating ARU-1801, a one-time potentially curative investigational gene therapy for patients with SCD. This Phase 1/2 study is currently enrolling participants, and information may be found at momentumtrials.comwhich includes a patient brochure, an eligibility questionnaireand information for healthcare providers.

About Jasper Therapeutics Jasper Therapeutics is a biotechnology company focused on the development of novel curative therapies based on the biology of the hematopoietic stem cell. The company is advancing two potentially groundbreaking programs. JSP191, a first-in-class anti-CD117 monoclonal antibody, is in clinical development as a conditioning agent that clears hematopoietic stem cells from bone marrow in patients undergoing a hematopoietic cell transplantation. It is designed to enable safer and more effective curative allogeneic and autologous hematopoietic cell transplants and gene therapies. In parallel, Jasper Therapeutics is advancing its preclinical engineered hematopoietic stem cell (eHSC) platform, which is designed to overcome key limitations of allogeneic and autologous gene-edited stem cell grafts. Both innovative programs have the potential to transform the field and expand hematopoietic stem cell therapy cures to a greater number of patients with life-threatening cancers, genetic diseases and autoimmune diseases than is possible today. For more information, please visit us at

About Aruvant Sciences Aruvant Sciences, part of the Roivant family of companies, is a clinical-stage biopharmaceutical company focused on developing and commercializing gene therapies for the treatment of rare diseases. The company has a talented team with extensive experience in the development, manufacturing and commercialization of gene therapy products. Aruvant has an active research program with a lead product candidate, ARU-1801, in development for individuals suffering from sickle cell disease (SCD). ARU-1801, an investigational lentiviral gene therapy, is being studied in a Phase 1/2 clinical trial, the MOMENTUM study, as a one-time potentially curative treatment for SCD. Preliminary clinical data demonstrate engraftment of ARU-1801 and amelioration of SCD is possible with one dose of reduced intensity chemotherapy. The company's second product candidate, ARU-2801, is in development to cure hypophosphatasia, a devastating, ultra-orphan disorder that affects multiple organ systems and leads to high mortality when not treated. Data from pre-clinical studies with ARU-2801 shows durable improvement in disease biomarkers and increased survival. For more information on the ongoing ARU-1801 clinical study, please visit http://www.momentumtrials.comand for more on the company, please visit Follow Aruvant on Facebook, Twitter @AruvantSciencesand on Instagram @Aruvant_Sciences.

About Roivant Roivant's mission is to improve the delivery of healthcare to patients by treating every inefficiency as an opportunity. Roivant develops transformative medicines faster by building technologies and developing talent in creative ways, leveraging the Roivant platform to launch Vants nimble and focused biopharmaceutical and health technology companies. For more information, please visit

SOURCE Aruvant Sciences andJasper Therapeutics


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Actinium Activates Radiation Inside the Body for Target Conditioning of Cancer Cells – Yahoo Finance

By daniellenierenberg

Actinium Pharmaceuticals Inc. (NYSE: ATNM), a clinical-stage biopharmaceutical company, is developing antibody radiation-conjugates (ARCs) to combine the targeting ability of antibodies with the cell-killing ability of radiation. The Company is a leader in the targeted radiotherapy field for cancer patients who cant tolerate chemotherapy and radiation. Actiniums lead asset, Iomab-B, is currently being studied in a pivotal Phase 3 clinical trial.

Standing out in the Field of Target Conditioning

What makes Actinium unique is in its novel approach to treatment options for cancer patients. According to the National Cancer Institute (NCI) a conditioning regimen may include chemotherapy, monoclonal antibody therapy and radiation to the entire body. It supports the patient's body to make room in the bone marrow for new blood stem cells to grow, helps prevent the body from rejecting the transplanted cells and assists with killing any cancerous cells. Actiniums targeted radiotherapies are intended to be focused missiles that hit cancer directly as opposed to a broader chemoradiation therapy that can hit many other areas that do not need to be attacked with such harsh treatments.

Among its competitors, Actinium remains the only company with a pivotal Phase 3 trial for a targeting conditioning agent and the only anti-CD45 ARC in clinical development.

Multiphase Clinical Trials and the Success of Iomab-B

In the ongoing Phase 3 SIERRA trial, Actiniums lead asset lomab-B acts as an induction and conditioning agent in patients over the age of 55 with relapsed or refractory acute myeloid leukemia (AML) prior to receiving a bone marrow transplant, also known as a hematopoietic stem cell transplant.

This multicenter trial is being conducted at over 20 leading transplant centers in the U.S., including MD Anderson, Memorial Sloan Kettering and Mayo Clinic.

Of all patients who received a therapeutic dose of Iomab-B, 100% proceeded to bone marrow transplant and engrafted, which is the first sign of success in contrast to the control arm, where only 18% of patients were able to go to transplant and engraft. Its a clear, marked difference, commented Actinium CFO Steve O'Loughlin.

Story continues

Additionally, Iomab-B was very well-tolerated. Minimal adverse effects and minimal nonrelapse transplant mortality were reported compared to the control arm, OLoughlin concluded.

In addition to Iomab-B, Actiniums drug development pipeline features Iomab-ACT, a lower dose of Iomab-B that is being studied for target conditioning in advance of CAR-T, a form of cellular therapy that weaponizes patients immune cells to attack and kill their cancer. Actinium is collaborating with Sloan Kettering to study Iomab-ACT with the institutes CD19 CAR-T therapy 19-28z in a Phase 1 trial in patients with relapsed or refractory leukemia. Actinium and Sloan Kettering have been jointly awarded grant funding from the National Institute of Health via its STTR Fast Track program.

Actiniums other clinical program, Actimab-A, which has been studied in a Phase 2 clinical trial, is now being studied in two Phase 1 combination trials: one with the salvage chemotherapy regimen CLAG-M and the other with Ventoclax, a targeted therapy jointly developed and marketed by AbbVie and Roche. Actinium is focused on continuing to expand its drug development pipeline by leveraging its Antibody Warhead Enabling (AWE) technology platform.

The AWE Technology Platform

Actinium is the leader in Ac-225-based therapies, the most powerful medical-grade radioisotope. This is a result of the Companys clinical experience, technology, intellectual property and know-how. The clinical experience encompasses over 500 patients who have been treated with Actiniums ARCs and through its clinical trials.

Actinium's AWE technology platform is used to produce ARCs, a highly potent and selective form of targeted radiotherapy. ARCs enable the precision targeting of radiation to tumors and its synergistic potential with other therapeutic modalities that cannot be matched by traditional external beam radiation, cytotoxic chemotherapy or biologic therapies.

AWE-enabled ARCs exploit the use of highly-selective targeted biological agents such as monoclonal antibodies that can seek out and bind cancer antigens found on the tumor cell surface. They deliver potent radioisotopes that are capable of producing double-strand DNA breaks for which there are currently no known resistance or repair mechanisms.

Actinium announced a collaborative research partnership with Astellas Pharma in 2018 to leverage Actiniums AWE technology platform with select Astellas targeting agents. In 2021, Astellas announced this collaboration will be focused on leveraging its select targeting agents to both image and diagnose cancers. The goal is to treat patients with Actiniums AWE technology platform using the Ac-225 radioisotope warhead.

2021 and Beyond

In 2020, Actinium became a fully-integrated, targeted radiotherapy development company by securing laboratory facilities in New York City. These new research facilities function under the guidance of Dale Ludwig, Ph.D., the Company's chief scientific and technology officer, who has over 25 years of oncology discovery research and development experience.

Currently, the SIERRA trial is being conducted at preeminent transplant centers in the U.S., and the Company has begun patient enrollment in the Phase I study of Iomab-ACT for targeted conditioning before treatment in collaboration with Memorial Sloan Kettering Cancer Center. Additionally, Actinium completed enrollment of a second dose cohort in its Actimab-A Venetoclax combination trial for patients with R/R AML, making this a very exciting year for the Company.

Actinium has an IP portfolio of over 140 patents. As of March 31, 2021, the Company had a cash balance of $72 million and as of May 18, 2021, it had a market cap of approximately $156 million. Visit for current news and more information.

Actinium is a partner of Benzinga. The information in this article does not represent the investment advice of Benzinga or its writers.

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Actinium Activates Radiation Inside the Body for Target Conditioning of Cancer Cells - Yahoo Finance

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Stem Cell Manufacturing Market Global Industry Analysis , Scope, Opportunity and Forecast 2020 to 2030 The Courier – The Courier

By daniellenierenberg

Global Stem Cell Manufacturing Market: Overview

Stem cells refer to special cells created by bone marrow of an individual. The key specialty of these cells is their ability to turn into various types of blood cells. Stem cells are gaining immense impetus owing to their key role in effectual disease management and specialized research activities including genomic testing and personalized medicine. Owing to these factors, the global stem cell manufacturing market is likely to register promising growth trajectory throughout the forecast period 20202030.

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The present research report performs segmentation of all the data gathered from the global stem cell manufacturing market into different sections. This segmentation is carried out based on many crucial parameters such application, product, end user, and region. Based on product, the market for stem cell manufacturing is classified into consumables, stem cell lines, and instruments.

Global Stem Cell Manufacturing Market: Growth Dynamics

Stem cells are used for various purposes such as clinical application, research applications, and cell and tissue banking applications. Thus, increased demand for the product from various end users including academic institutes, pharmaceutical and biotechnology companies, hospitals and surgical centers, cell and tissue banks, and research laboratories and contract research organizations is likely to generate lucrative avenues for vendors in the global stem cell manufacturing market in the years ahead.

Over the period of past few years, there is extensive growth in awareness pertaining to the therapeutic effectiveness of stem cells. This factor is working in favor of the expansion of the global stem cell manufacturing market. Owing to the restricted therapeutic treatment options for orphan diseases, there is considerable growth in investments toward stem cell-based technologies development by private as well as public stakeholders. This scenario is expected to help in rapid growth of the global stem cell manufacturing market in the years to come.

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Global Stem Cell Manufacturing Market: Competitive Analysis

Owing to presence of many active players, the nature of stem cell manufacturing market seems to be highly fragmented. It also denotes the high level of competition in the market for stem cell manufacturing. Thus to sustain in this high competitive scenario, enterprises are executing different strategic moves including collaborations, partnerships, mergers, acquisitions, agreements, joint ventures, and new product launches. Apart from growing financial support toward research and development activities, many players working in the stem cell manufacturing market are strengthening their production capabilities. On the back of all these moves, we can conclude that the global stem cell manufacturing market will expand at moderate pace throughout the assessment period 20202030.

Global Stem Cell Manufacturing Market: Notable Development

In May 2021, University of California, San Francisco and Thermo Fisher Scientific entered into strategic alliance. The main motive of this alliance was to open cell therapy cGMP manufacturing and collaboration center.The list of important players in the global stem cell manufacturing market includes:

Merck MilliporeThermo Fisher ScientificDanaher CorporationLonza Group AGBio-Rad LaboratoriesSartorius AGStemcell TechnologiesMiltenyi BiotecFujifilm Holdings CorporationCellgenix GMBHGlobal Stem Cell Manufacturing Market: Regional Assessment

In terms of region, the global stem cell manufacturing market is spread across many regions such as Europe, North America, Latin America, the Middle East and Africa, and Asia Pacific. Of these regions, North America is one of the prominent regions in the market for stem cell manufacturing. Key factor supporting this growth include extensive research and development in the region together with increased financial support by government as well as no-government organizations for the study of stem cell applications.

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Stem Cell Manufacturing Market Global Industry Analysis , Scope, Opportunity and Forecast 2020 to 2030 The Courier - The Courier

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Hematopoietic Stem Cell Transplantation (HSCT) Market Competitive Analysis with Global Trends and Demand 2021 to 2028:ViaCord Inc, Cryo-Save AG, CBR…

By daniellenierenberg

Global Hematopoietic Stem Cell Transplantation (HSCT) Market Size, Status And Forecast 2021-2028

MarketInsightsReports, a leading global market research firm, is pleased to announce its new report on Hematopoietic Stem Cell Transplantation (HSCT) market, forecast for 2021-2028, covering all aspects of the market and providing up-to-date data on current trends.

The report covers comprehensive data on emerging trends, market drivers, growth opportunities, and restraints that can change the market dynamics of the industry. It provides an in-depth analysis of the market segments which include products, applications, and competitor analysis. The report also includes a detailed study of key companies to provide insights into business strategies adopted by various players in order to sustain competition in this highly competitive environment.

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With our Hematopoietic Stem Cell Transplantation (HSCT) market research reports, we offer a comprehensive overview of this sector and its dynamics. We have done extensive research on this topic and are confident that our findings will be helpful for anyone who needs some guidance or direction when making important decisions related to their companys future growth strategy.

Top Companies in the Global Hematopoietic Stem Cell Transplantation (HSCT) Market: ViaCord Inc, Cryo-Save AG, CBR Systems Inc, Pluristem Therapeutics Inc, China Cord Blood Corp, Lonza Group Ltd, Escape Therapeutics Inc, Regen Biopharma Inc

This report segments the global Hematopoietic Stem Cell Transplantation (HSCT) market on the basis of Types are:

On the basis of Application, the Global Hematopoietic Stem Cell Transplantation (HSCT) market is segmented into:

For comprehensive understanding of market dynamics, the global Hematopoietic Stem Cell Transplantation (HSCT) market is analyzed across key geographies namely: United States, China, Europe, Japan, South-east Asia, India and others. Each of these regions is analyzed on basis of market findings across major countries in these regions for a macro-level understanding of the market.

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Key Takeaways from Hematopoietic Stem Cell Transplantation (HSCT) Report

Browse the report description and TOC:

-Key Strategic Developments: The study also includes the key strategic developments of the market, comprising R&D, new product launch, M&A, agreements, collaborations, partnerships, joint ventures, and regional growth of the leading competitors operating in the market on a global and regional scale.

-Key Market Features: The report evaluates key market features, including revenue, price, capacity, capacity utilization rate, gross, production, production rate, consumption, import/export, supply/demand, cost, market share, CAGR, and gross margin. In addition, the study offers a comprehensive study of the key market dynamics and their latest trends, along with pertinent market segments and sub-segments.

-Analytical Tools: The Global Hematopoietic Stem Cell Transplantation (HSCT) Market report includes the accurately studied and assessed data of the key industry players and their scope in the market by means of a number of analytical tools. The analytical tools such as Porters five forces analysis, SWOT analysis, feasibility study, and investment return analysis have been used to analyze the growth of the key players operating in the market.

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MarketInsightsReports provides syndicated market research on industry verticals including Healthcare, Information and Communication Technology (ICT), Technology and Media, Chemicals, Materials, Energy, Heavy Industry, etc.MarketInsightsReports provides global and regional market intelligence coverage, a 360-degree market view which includes statistical forecasts, competitive landscape, detailed segmentation, key trends, and strategic recommendations.

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Hematopoietic Stem Cell Transplantation (HSCT) Market Competitive Analysis with Global Trends and Demand 2021 to 2028:ViaCord Inc, Cryo-Save AG, CBR...

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Brave Nathaniel Nabena, 9, all smiles as he has life-saving procedure – thanks to you – The Mirror

By daniellenierenberg

Brave Nathaniel Nabena smiles from his hospital bed moments before a life-saving procedure.

The nine-year-old had a vital stem cell transplant at Great Ormond Street Hospital on Wednesday after Sunday People readers helped raised more than 215,000.

Nathaniel, battling acute myeloid leukaemia, was on a drip for 30 minutes as umbilical cord stem cells were fed into his body.

Afterwards, dad Ebi said: Nathaniel is very happy. It was amazing to finally get to this point we have all been waiting for.

The youngster was admitted a fortnight ago and had five doses of chemo over ten days to prepare him for the procedure.

How brave has Nathaniel been? Have your say in comments below

Mum Modupe, 38, was able to spend time with him before his transplant.

Consultants warn he faces weeks of sickness as his body reacts to the new cells with symptoms including vomiting and a fever.

Ebi, 45, said: His doctors hope to see improvements after five weeks. It is so hard to see him so exhausted but I dont have a choice. We are grateful to have this done. Our fingers are crossed to see what happens.

For now, Nathaniel has a compromised immune system and is susceptible to falling ill, so he will be staying on the ward.

Stars including Simon Cowell, David Walliams, Katie Price and JLS singer Aston Merrygold rallied to support him after we told of the desperate race to fund treatment.

Nathaniels left eye was removed in his home country of Nigeria a year ago, due to myeloid sarcoma cancer. He was diagnosed with AML in the UK in November after coming here to have a prosthetic eye fitted.

Nathaniel was told a stem-cell transplant was his only hope for survival but it would cost 201,000 as he is not a British citizen. Ebi and Modupe were initially told it could cost as much as 825,000 but the figure was revised after doctors waived their fees and offered to treat him in their own time.

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The lad was admitted to GOSH on May 24 after generous Brits rushed to help the family raise cash.

Business analyst Ebi, who is staying at the hospitals family quarters, said: Ive been there the whole time. When he is not sleeping he is passing the time playing his games.

We sometimes talk about when he gets better and how exciting that will be. This is a difficult thing for him to go through, but Nathaniel is being brave, he is well in himself.

In acute myeloid leukaemia, unhealthy blood-forming stem cells grow quickly in the bone marrow.

This prevents it from making normal red blood cells, white blood cells and platelets meaning the body cannot fight infections or stop bleeding.

A stem cell transplant, also known as a bone marrow transplant, can help AML patients stimulate new bone marrow growth and restore the immune system.

Before treatment, patients need high doses of chemo and sometimes radiotherapy.

This destroys existing cancer and bone marrow cells and stops the immune system working, to cut the risk of transplant rejection.

In an allogeneic transplant, stem cells are taken from a family member, unrelated donor or umbilical cord blood. In Nathaniels case, it was from a cord.

They are then passed into the patients body through a line inserted in a large, central vein, in a process that takes up to two hours.

You can also remove stem cells from the patients body and transplant them later, after any damaged or diseased cells have been removed this is called an autologous transplant.

The survival rate after a transplant for patients with acute leukaemia in remission and using related donors is 55% to 68%, according to Medicine Net. If the donor is unrelated, it is 26% to 50%.

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BioRestorative Therapies to Present at the Emerging Growth Conference on June 9, 2021 –

By daniellenierenberg

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BioRestorative Therapies invites individual and institutional investors, as well as advisors and analysts, to attend its real-time, interactive presentation at the online Emerging Growth Conference.

MELVILLE, N.Y., June 07, 2021 (GLOBE NEWSWIRE) -- BioRestorative Therapies, Inc. (the Company or BioRestorative) (OTC: BRTX), a life sciences company focused on stem cell-based therapies, is pleased to announce that it is has been invited to present at the online Emerging Growth Conference on June 9, 2021.

The Emerging Growth Conference will be held on June 9, 2021. This live, interactive online event will give existing shareholders and the investment community the opportunity to interact with the Companys CEO, Lance Alstodt, and Vice President of Research and Development, Francisco Silva, in real time.

Mr. Alstodt will make a presentation and answer questions. Please ask your questions during the event and Mr. Alstodt will try to respond to as many as possible.

BioRestorative Therapies will be presenting at 10:45 AM Eastern time for 45 minutes.

Please register here to ensure you are able to attend the conference and receive any updates that are released:

If attendees are unable to join the event live on the day of the conference, an archived webcast will also be made available on, and the Company will also release a link to that site after the event.

About the Emerging Growth Conference

The Emerging Growth Conference is an effective way for public companies to present and communicate their new products, services and other major announcements to the investment community from the convenience of their office, in a time efficient manner.

The Conferences focus and coverage includes companies in a wide range of growth sectors, with strong management teams, innovative products and services, focused strategy, execution, and the overall potential for long term growth. Its audience includes potentially tens of thousands of individuals and institutional investors, as well as investment advisors and analysts.

All sessions will be conducted through video webcasts and will take place in the Eastern time zone.

About BioRestorative Therapies, Inc.

BioRestorative Therapies, Inc. ( develops therapeutic products using cell and tissue protocols, primarily involving adult stem cells. Our two core programs, as described below, relate to the treatment of disc/spine disease and metabolic disorders:

Disc/Spine Program (brtxDISC): Our lead cell therapy candidate, BRTX-100, is a product formulated from autologous (or a persons own) cultured mesenchymal stem cells collected from the patients bone marrow. We intend that the product will be used for the non-surgical treatment of painful lumbosacral disc disorders or as a complementary therapeutic to a surgical procedure. The BRTX-100 production process utilizes proprietary technology and involves collecting a patients bone marrow, isolating and culturing stem cells from the bone marrow and cryopreserving the cells. In an outpatient procedure, BRTX-100 is to be injected by a physician into the patients damaged disc. The treatment is intended for patients whose pain has not been alleviated by non-invasive procedures and who potentially face the prospect of surgery. We have received authorization from the Food and Drug Administration to commence a Phase 2 clinical trial using BRTX-100 to treat chronic lower back pain arising from degenerative disc disease.

Metabolic Program (ThermoStem): We are developing a cell-based therapy candidate to target obesity and metabolic disorders using brown adipose (fat) derived stem cells to generate brown adipose tissue (BAT). BAT is intended to mimic naturally occurring brown adipose depots that regulate metabolic homeostasis in humans. Initial preclinical research indicates that increased amounts of brown fat in animals may be responsible for additional caloric burning as well as reduced glucose and lipid levels. Researchers have found that people with higher levels of brown fat may have a reduced risk for obesity and diabetes.

Forward-Looking Statements

This press release contains "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and such forward-looking statements are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. You are cautioned that such statements are subject to a multitude of risks and uncertainties that could cause future circumstances, events or results to differ materially from those projected in the forward-looking statements as a result of various factors and other risks, including, without limitation, those set forth in the Company's latest Form 10-K filed with the Securities and Exchange Commission. You should consider these factors in evaluating the forward-looking statements included herein, and not place undue reliance on such statements. Any forward-looking statements in this release are made as of the date hereof and the Company undertakes no obligation to update such statements.


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Regenerative medicine: moving next-gen treatments from lab to clinic – Pharmaceutical Technology

By daniellenierenberg

The investment in bolstering defences in virtual space also remains a top priority, as the pharmaceutical industry is extremely susceptible to cyber-attacks due to the involvement of sensitive and valuable data.

Several pharmaceutical companies and research institutes including Hammersmith Medicines Research in the UK, the University of California, San Francisco (UCSF), and US-based clinical services company eResearch Technology (ERT) remained targets for cyberattacks due to their involvement in the development of COVID-19 vaccines.

GlobalData conducted to survey to assess to extent to which emerging technologies such as cybersecurity will help a company survive through the Covid-19 pandemic.

Analysis of the results found that 54% of the respondents opined that cybersecurity would play a significant role in helping companies to pull through the crisis created by the pandemic.

Cybersecuritys Role During COVID-19 Crisis

Another 33% of the surveyed companies expect cybersecurity to play a minor role during the COVID-19 crisis.

Further, 10% of the companies stated that cybersecurity will play no role during the pandemic, while 3% of the respondents were unaware of the impact of cybersecurity.

The analysis is based on responses received in GlobalData, Emerging Technologies Survey 2020 fielded between 29 May and 09 July 2020.

Customised Viral Vectors for Cell Modelling, Gene Therapy, and Vaccination Research and Development

28 Aug 2020

Pharmaceutical-Grade Water Purification Systems for the Pharmaceutical and Biopharma Markets

28 Aug 2020

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Living with blood cancer – Lara Said – Times of Malta

By daniellenierenberg

World Blood Cancer Day is marked today. The celebration of this day was instituted in 2014 because, in 1991, Methchild Ehringer could not find a match by a German non-profit organisation DKMS founded by Methchilds family. She died because she was unable to find a match. The aim was and still remains to find a potential donor for every person needy of a bone marrow/stem cell transplant.

Today, there are 10 million potential donors registered when compared to the initial 3,000. Some might remember me as the person who needs Daratumumab included in the government formulary for free medicinals. I am interested in other matters too!

World Blood Cancer Day! This day highlights a more personal issue that concerns the realisation that I do not stand alone in my blood cancer journey. An issue that cuts across the three most common blood cancers: leukaemia, lymphoma and myeloma. Of these three, the lymphomas and the myelomas are the more common. For many people, such as myself, the diagnosis of a blood cancer is a shock. Like water, blood is meant to sustain a person.

Blood cancers bring along with them a lot of uncertainty and anxiety. For some blood cancers, such as multiple myeloma, a cure does not exist. To suddenly acknowledge that what is being generated in your bone marrow and what is circulating around your body and through your own blood is threatening you and your body, is psychologically invasive in a way like no other. I felt robbed. Robbed by my own body, my own immune system and, perhaps, by my own past lifestyle choices.

Stem cell transplantation offers hope of increased longevity, when appropriate, to a good proportion of blood cancer patients. A successful stem cell transplant means time out of hospital, visiting usually only every few months for monitoring. There are two types of stem cell transplantation: autologous and allogenic.

Autologous transplantation is when a person donates to oneself. As was the case with myself and my two attempts for autologous transplantation.

For many people, such as myself, the diagnosis of a blood cancer is a shock

Allogenic requires matching a donor to a patient. This is only suitable in specific cases. The government of Malta does pay for such transplantation. Charities such as Puttinu are incredibly supportive in supporting those undergoing stem cell transplantation by providing accommodation. On World Blood Cancer Day 2021, my wish is that the Maltese public understand what I consider to be three critical issues.

First, for many, stem cell/bone marrow transplants and, increasingly, cellular innovative therapies, potentially require a donor. Second, for a portion of those requiring such intervention/therapy they cannot donate to themselves and/or find a donor from their family. Third, millions of people are required to donate their stem cells.

As of today, I am under the impression that Malta and its generally very good healthcare system does not yet, have a register for stem cell donation. I hope I am wrong. Should I be right, I urge the powers that be to strongly consider this as part of their long-term strategic vision. What I do know, however, is that Malta has the local expertise and the equipment to collect stem cell transplants.

Perhaps because it is a small-island state, Malta does not have the facility for storage. The healthcare system is probably likely, especially at this point in time, not to possess as much capacity to assure consistent and sustained storage of stem cells according to European and international gold-standard criterion. This is likely to be primarily due to space issues given that the local expertise is available and excellent.

In more recent times especially, monoclonal agents, such as Daratumumab, are increasingly offered as more frontline treatment to those with an early diagnosis of multiple myeloma, at least in other EU countries and to those able to afford payment.

Chimeric Antigen therapy (CAR-T cell), which forms part of cellular therapeutic options, is also in the pipeline.

Monoclonal therapy and CAR-T cell are consequently likely to decrease the need for stem cell transplants. This is positive but, if anything, highlights even more the need for a stem cell database, register and repository. Newer therapies generally tend to be increasingly stem cell therapy dependent in some form or other.

What I would like the reader to appreciate is that I am not a medical professional. I have been at times accused of being a dreamer but life has taught me two things.

To turn lemons into lemonade and to give without the expectation of taking or receiving.

Today, I would like to go a bit beyond my myeloma, so to speak. I want to celebrate, as a blood cancer survivor, what works for me. I urge all of you to read about blood cancers and try to empathise with all blood cancer survivors.

Above all, let us not forget their carers: spouses, children, friends, doctors, nurses and everybody else whom I have inadvertently omitted.

I, for one, would not be here, especially, without the excellent care and patience of doctors, nurses, physiotherapists, etc. alongside the emotional care, motivation and interest offered by my sons, friends, work colleagues and those generally understanding and supportive of my condition, and, yes, my Lara still needs Dara quest! Thank you.

Lara Saids dream is to set up a non-profit organisation to advocate especially for the rights of patients with myeloma, leukaemia and lymphoma for Malta and Gozo. She is here appealing to survivors, their relatives and/or carers to help her set up a patient group.

Lara Said, Multiple myeloma survivor, member, Myeloma Patients Europe

Independent journalism costs money. Support Times of Malta for the price of a coffee.

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Stem Cell vs Gene Therapy Processes in SCD – MD Magazine

By daniellenierenberg

Ifeyinwa Osunkwo, MD, MPH: Pat, can you describe the steps people go through to do a bone marrow transplant to gene therapy? Set the stage to help people understand why busulfan and why were talking about mutations. Can you walk us through the whole gene therapy process?

Patrick McGann, MD, MS: With transplant or gene therapy, the term transplant could be autologous, meaning your own cell gene therapy transplant. Its not as if youre transplanting a solid organ or a kidney. Sometimes patients get confused about this. Its looks like a blood transfusion hanging when it eventually goes in. For a bone marrow transplant, the donorwhoever that iseither gets a bone marrow aspiration, where they get bone marrow cells taken from their bone marrow, or a medicine to rev up their blood cells and get blood taken just from their vein. The patient needs to get prepared because they need to get rid of all their sickle cells. They need to suppress their immune system, so they dont reject this foreign cell, which is someone elses.

We use strong chemotherapy. If you have leukemia, as a comparison, you need to kill every last leukemia cell, and you get blasted with really strong chemotherapy agents and strong immunosuppressive agents. This is usually a week or so before; the days are counted backward. The cells that go in your body are most vulnerable to infection to everything. Its a dangerous time. Thats when complications come in. If its a transplant, you get infused with that donors bone marrow cells and hope it takes. It takes some weeks time for your body to take those new cells, and youre often receiving antibiotics and getting transfused and sustaining it, because your bone marrow is still not working. Basically, your immune system is suppressed. Its a tough time.

Transplant conditioning, as this regimen is called, has gotten a little less toxicreduced conditioning is the term. But thats still serious conditioning. Even though its reduced from what it used to be, its a relative term. Gene therapy is a little different because youre giving back your own cell. The way gene therapy happens is its ex vivo, meaning they take it out of your body. There are different ways that this is being done. Many patients need to have a bone marrow aspiration or many procedures to take enough cells out of their bone marrow to take them to the lab to fix them. There have been new ways to do this with peripheral blood and a medication called plerixafor, which is much better than going to the operating room for these horrible procedures.

Those cells are then taken to the lab and edited, or whatever the mechanism of gene therapy is. You still need to ablate your bone marrow to get rid of all your sickle cells. Because if you have any or many sickle cells in there, when you give back your edited gene cells, those will just take over. You still need to suppress that bone marrow. Because its your own cells, the immune suppression isnt as much of a problem as it is with transplant. Still, its a week of pretty serious medicinebusulfan, traditionallyand youre in the hospital for less of a period of time than transplant. Its quite an ordeal. Similarly, it takes or doesnt, and you monitor over time if that gene therapy has worked and whether its sustainablecross your fingersin the long term.

Ifeyinwa Osunkwo, MD, MPH: Basically, you have 2 options. The first option, you have to kill off their own bone marrow cells using chemotherapy. Then you give them somebody elses bone marrow, like a blood transfusion. The stem cells from the other person finds its way into their bone marrow and then grows. Then you wait and see what happens. Do you fight it? Do you accept it? We know if it takes or not. For gene therapy, we take out the patient stem cells, take it to a laboratory. Its usually in New Jerseydont ask me why. They manipulate it to pick out the gene they dont want. Then they give that patient back their own modified stem cells and wait for it to grow. But you still have to wipe out that persons bone marrow, so you dont have this fight going on. Even though theyre your cells, theyre a little different with the new gene change that has been made. Its a complicated process, and its really the only way to cure your disease. Either stem cell or gene therapy. We have had some setbacks in the past and more recently, but I believe that science is going to prevail. Over time were going to get to the point where we figure out the way to do this in the safest way to make it available to the most people with sickle cell disease and other blood disorders.

Thank you so much for watching this HCPLive Peer Exchange. If you enjoyed the content, please subscribe to the e-newsletter to receive upcoming Peer Exchanges and other great content right in your in-box.

Transcript Edited for Clarity

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‘Lion-hearted’ ten-year-old Aurora’s ‘second chance’ at life after cancer remission and stem cell transplant – The Isle of Thanet News

By daniellenierenberg

Fighter: A year long battle but Rory is still smiling

In January 10-year-old Aurora Pile-Grays family were told they may lose their little girl as a rare and aggressive cancer took its devastating toll.

The previous November Aurora affectionately known as Rory had been declared in remission from the disease that she had been fighting since May 2020 but a cruel blow saw a severe relapse with the cancer progressing to her skull, eyes, neck, spine, liver, kidneys, lungs, abdomen and pelvis.

A discussion with the consultant over going home from hospital and preparing for end of life care took place but lion-hearted Rory was not ready to give up her fight against Burkitts Lymphoma which affects blood and bone marrow and her family were not ready to let go.

After a year-long battle with the disease, seven rounds of intensive chemotherapy, stays in Royal Marsden and Great Ormond Street hospitals and targeted therapy with trial drug Inotuzumab, Aurora was declared cancer free again at the end of April.

The Inotuzumab drug also offered the family, who live in Garlinge, a chance for Aurora to be at home despite treatment.

Mum Keisha, 28, said: We chose Inotuzumab because it meant a better quality of life for Rory, she could come home to us and her brother and sister rather than having to be in hospital.

The trial drug, and cancer all clear, opened the way for the youngster to undergo a bone marrow transplant on May 13 all the more vital as chemo had wiped out her immune system.

First there were 10 radiotherapy sessions to get through involving cranial boost, where Auroras face was bolted to the bed so she couldnt move.

The transplant which is universally referred to as a new birthday to signal a second chance at life took place at the Marsden and involved replacing old bone marrow cells that are failing to produce healthy new cells, with cells from a donor. The aim is to create a new immune system and hopefully prevent cancer returning or mutations occurring.

The stem cells Aurora now carries should begin to reproduce in her own body and allow her bone marrow to work as normal in producing healthy red cells, white cells and platelets, since her body is no longer capable of doing so after the effects of both the cancer and the treatment.

Auroras donor cells were frozen in December which meant on the day they had to be defrosted and infused within 20 minutes. Auroras donor produced nine bags of stem cells. Only four were required, leaving 5 for future use if needed.

Each bag is defrosted in a water bath around 38 degrees so that by the time its infused its not too different to body temperature. They are then put into separate syringes and pushed through a central line into the body.

The family have been told there is just a 10-20% chance that the transplant will achieve long lasting remission, but the St Crispins school youngster has so far beaten the odds and mum Keisha says her little girl is a fighter.

In her blog Growing Pains and Paper Planes, Keisha says: Shes been amazing throughout this entire journey and Im unbelievably proud to call her my daughter. Im in awe of her strength, determination and resilience and shes shown us all that sometimes the smallest hearts overcome the biggest battles.

So far Aurora has responded well to the transplant and there is evidence of engraftment where the donor cells find their way to her bone marrow and begin to make new blood cells. White cells are the first to engraft which include neutrophils, then red cells and then platelets.

Keisha said: We were worried the effects would be awful as Rory was so sensitive to the chemo but it is going really well.

Rory is up every day, listening to audio books and doing lots of colouring, cracking jokes and just being Rory.

It is such a relief. In January when we realised the cancer had spread and she could lose the use of her legs, bladder and bowel we had to talk about making her comfortable at home. But we were not ready to give up. I said it wasnt that time yet, not all the time that Rory was laughing and joking and looking forward to seeing her brother and sister. She wasnt giving up and we werent.

Now there has been this complete 360 turnaround. Everything still depends on how she takes to the transplant. On day 28 a sample will hopefully show what percentage are donor (cells) and what percentage are her own. Hopefully it will show primarily donor.

Rory is on immunosuppressants for up to a year but potentially could be able to return to school in six months time.

Keisha said: Shell go back as a Year 6 and has missed two years but has been doing schoolwork for an hour each day.

She is looking forward to it, more the social side than the work!

Rory has won the hearts of the Thanet community during her battle with cancer with many following the familys progress through Keishas blog and also donating to a fundraiser for life-saving treatment. People also signed up on the bone marrow register following Keishas highlighting of the desperate need for donors, especially people of mixed ethnicity.

Keisha said: We are unbelievably grateful and humbled by the support people have shown us over the past year. The kind words, the gestures, the gifts, the donations, the shares, the marrow registrations and the sense of community has helped us more than you will ever know.

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Chronic lymphocytic leukemia and stomach pain: What is the link? – Medical News Today

By daniellenierenberg

Chronic lymphocytic leukemia (CLL) is a type of blood cancer. It affects lymphocytes, a type of immature white blood cell that the body produces in the bone marrow.

People with CLL may experience discomfort, swelling, and pain in the abdomen if their spleen enlarges. In rare cases, CLL can also affect mucosal tissues, such as those lining the gastrointestinal (GI) tract.

This article discusses the link between CLL and stomach pain in more detail. It also looks at ways to prevent and treat CLL, the other possible symptoms, and the outlook for people with this condition.

People with CLL may experience various symptoms involving the abdomen or stomach, such as:

In most cases, people with CLL do not experience abdominal symptoms due to the disease until it progresses and becomes more severe.

Research suggests that CLL infiltrates and affects the GI tract in about 5.713% of cases. When CLL affects the GI tract, doctors may call it Richters syndrome.

People with CLL may experience abdominal swelling, discomfort, and tenderness as a result of their spleen becoming larger. Less commonly, they may also feel full after eating small amounts of food, as the spleen can press on the stomach, making it smaller and able to hold less.

In rare cases, CLL infiltrates the lining of the GI tract, causing inflammation and ulcers or open wounds. People may experience symptoms similar to those of inflammatory bowel disease (IBD) and malabsorption disorders. These symptoms may include diarrhea, nausea, vomiting, abdominal pain and cramping, and unintentional weight loss.

CLL is cancer that develops in lymphocytes, which are white blood cells that form in the bone marrow and help fight infection.

Lymphocytes make up most of the lymph tissues in the lymph nodes, thymus gland, adenoids, tonsils, and spleen. They are also present in the GI tract, bone marrow, and respiratory system.

CLL is a type of leukemia that develops gradually over time.

About 5075% of people with CLL do not experience noticeable symptoms. Due to this, doctors diagnose most people with CLL during routine blood work.

The symptoms of CLL often begin when the cancerous cells crowd out healthy cells in the bone marrow or migrate to other organs or tissues. When symptoms first appear, they are typically mild, but they then become increasingly severe. CLL can cause many nonspecific symptoms, so a person may feel as though they have a cold or the flu.

Possible symptoms of CLL that do not relate to the abdominal area include:

Doctors do not yet have a way to prevent leukemia. However, some types of leukemia, including CLL, may have links to toxins, such as herbicides, pesticides, radon, and tobacco exposure. People can help reduce the risk of CLL by avoiding or practicing extreme caution around these toxins.

Many people do not experience symptoms of CLL for years and do not require treatment. However, as the disease progresses, these individuals may need treatment to extend their lives.

When and how a doctor treats someones CLL depends on a few factors, including:

Chemotherapy is typically the first-line therapy for CLL.

Doctors may use chemotherapy in conjunction with other treatment options, such as monoclonal antibody therapy. This therapy binds antibodies to cancer cells and destroys them. Treatment can also include medications to treat or prevent infections or improve low blood cell levels.

For instance, some people may take a combination of the monoclonal antibody rituximab and the chemotherapy drugs fludarabine and cyclophosphamide. Alongside the oral chemotherapy medication chlorambucil, doctors use obinutuzumab or ofatumumab, which have the same drug target as rituximab.

Small molecule inhibitors, such as bendamustine hydrochloride, idelalisib, and ibrutinib, can also sometimes form part of a CLL treatment regimen.

In 2017, the Food and Drug Administration (FDA) approved the combination medication Rituxan Hyecela (rituximab and hyaluronidase human) for CLL treatment.

In recurring or aggressive cases of CLL, an individual may have a blood or bone marrow stem cell transplant. This procedure replaces diseased cells with healthy blood cells that are able to mature into bone marrow cells.

Doctors may treat CLL until the symptoms lessen and then stop treatment until the symptoms worsen again.

Many people with CLL live for many years with a high quality of life.

There is no cure for CLL, so treatment aims to extend and improve someones life by reducing their symptoms. Doctors treat many people intermittently as their symptoms reoccur.

A persons outlook depends on their age, overall health, underlying conditions, and stage of CLL. Typically, people who are over the age of 65 years or have a more advanced stage of CLL have a less positive outlook.

Genetic changes in CLL cells and increased beta-2 microglobulin protein levels in the blood can make CLL more challenging to treat, potentially affecting a persons outlook.

Doctors classify people with CLL into different risk groups depending on certain factors. Based on these risk groups, the estimated percentages of people surviving 5 years or more after their diagnosis is:

People with more advanced or severe CLL may experience abdominal swelling, discomfort, tenderness, and pain. They may also feel full after eating small amounts. More rarely, someone with CLL may develop GI tract inflammation or ulcers, which can cause symptoms such as diarrhea, nausea, vomiting, cramping, and unexplained weight loss.

Anyone who thinks that they may have CLL should speak with a doctor. People with a confirmed diagnosis who experience symptoms of more advanced or severe CLL, such as abdominal pain, should also seek medical care.

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Magenta Therapeutics’ research lead Davis hits the exit for family reasons – FierceBiotech

By daniellenierenberg

Magenta Therapeutics is losing its chief medical officer and head of R&D John Davis, M.D., with his last day coming July 30.

Davis helped steer the biotechs early path as well as deals with Avrobio and base editing biotech Beam Therapeutics around its lead stem cell conditioning program, MGTA-117, and MGTA-145 as a potentially new first-line standard of care for stem cell mobilization in a broad range of diseases. His departure comes three years after he joined the company from Pfizer, where he led its early R&D.

The biotech was keen to stress in an 8-K SEC filing (but not a press release) that his departure was not related to any disagreements with the Company on any matter relating to its operations, policies, practices or any issues regarding financial disclosures, accounting or legal matters.

It will now look for a new CMO, while Davis will become an adviser to the company.

RELATED: Magenta CSO Cooke jumps to IFM Therapeutics

This isnt the first move within the R&D ranks: Magenta started 2020 by losing its chief scientific officer when Michael Cooke, Ph.D., hopped over to IFM Therapeutics. In the fall, though, it nabbed Lisa Olson, Ph.D., who previously led immunology discovery at AbbVie, as his replacement.

Conditioning is a necessary step for some gene therapies, but one that can cause side effects like nausea, hair loss and mouth sores or make patients more vulnerable to infection. Magentas platform is based on looking to improve on current methods with an antibody-drug conjugate.

MGTA0117 is made up of an anti-CD117 antibody linked to amanitin, a cell-killing toxin. It is designed to target only hematopoietic, or blood-forming, stem cells and progenitor cells.

Animal studies suggest it could clear space in bone marrow for gene-modified stem cells to take root, Magenta said. The company plans to wrap IND-enabling studies for the antibody-drug conjugate this summer.

MGTA-145, meanwhile, just finished off a midstage test earlier this month, hitting its primary endpoint in a small multiple myeloma study.

Davis' replacement will already have a lot of clinical work on their hands.

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Moderna Highlights Advances in Platform Science and Innovative Vaccine Research at Fourth Annual Science Day – Business Wire

By daniellenierenberg

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Moderna, Inc., (Nasdaq: MRNA) a biotechnology company pioneering messenger RNA (mRNA) therapeutics and vaccines, today announced new research being highlighted as part of the Companys fourth annual Science Day. Modernas Science Day is designed to provide insight into the continued diverse efforts underway at Moderna to better understand how to use mRNA as medicines and vaccines and underscores the Companys continued commitment to basic science and innovation.

Science Day gives us an opportunity to provide insights into the advancements in our platform science and our further understanding of how to use mRNA as both a vaccine and a medicine. Our investments in basic science continue to result in major steps forward in our platforms capabilities, and these have allowed us to open new therapeutic areas and new scientific directions, said Stephen Hoge, M.D., President of Moderna. Our investments in platform research along with our digital backbone and manufacturing plants have enabled us to create first-in-class mRNA medicines and vaccines. Today, we're excited to highlight our work to identify and address SARS-CoV-2 variants of concern, optimize our proprietary lipid nanoparticle (LNP) technology, and deliver mRNA to hematopoietic stem cells.

Moderna currently has 24 mRNA development programs in its portfolio with 14 having entered clinical studies. The Companys updated pipeline can be found at Moderna and collaborators have published more than 65 peer-reviewed papers.

At this years Science Day, Moderna will present new platform science and preclinical research, including:

mRNA Delivery to Hematopoietic Stem and Progenitor Cells (HSPC)

Of the nearly 30 trillion cells in the body, approximately 90% are of hematopoietic origin. Hematopoietic lineages originating in the bone marrow are intimately involved in maintaining homeostasis and human health. Nonetheless, there are hundreds of hematologic or immune-related disorders caused or exacerbated by cells of the hematopoietic lineage. In a disease setting, cells of hematopoietic origin interact with host tissues to drive chronic inflammatory and immune disorders. Because some hematopoietic stem and progenitor cells (HSPC) have self-renewal and pluripotent properties, targeting HSPC has the potential to modulate underlying chronic inflammation and immune-related disorders.

Advances in lipid nanoparticle (LNP) technology has allowed for delivery to the bone marrow following systemic LNP administration in vivo. This achievement has enabled Moderna scientists to deliver mRNA directly to bone marrow HSPC in vivo, leading to HSPC transfection and long-term modulation of all hematopoietic lineages. This represents a major milestone in impacting chronic inflammatory and immune related disease.

mRNA Engineering: Optimizing Ribosome Load

The ribosome plays a central role in orchestrating the life of mRNA inside the cell. Understanding how to modulate translation by changing mRNA sequence could enable a powerful lever to control the performance of an mRNA drug. To develop such a lever, the Moderna's scientists strove to characterize mechanistically how differences in translation drive differences in protein expression. In this research, an unexpected relationship emerged where mRNAs with low translation initiation rates conferred the highest and most durable levels of protein expression. By understanding the mechanisms that drive this behavior, the Company is taking mRNA design from a guess-and-check discipline into an engineering discipline. With tools in place, and more under development, Moderna is improving its ability to make an mRNA that generates the right amount of the right protein, for the right amount of time, in the right cell type. As Moderna builds these levers into its mRNA drugs, the Company believes it will be able to target more indications with more precision.

Addressing SARS-CoV-2 Variants of Concern

One part of the Companys strategy to remain ahead of the SARS-CoV-2 virus is to closely monitor and address emerging variants of concern and waning immunity. Moderna is using artificial intelligence (AI) and machine learning to predict escape risk. This involves developing statistical models to understand and predict escape risk, including identifying breakthrough sequences from clinical trials and real-world data, examining spike protein biophysical and pseudovirus neutralization data, studying spike mutations and lineage info, and time tracking.

Science Day Webcast Information

Moderna will host its annual Science Day for analysts and investors at 8:00 a.m. ET on Thursday, May 27. A live webcast will be available under Events and Presentations in the Investors section of the Moderna website at A replay of the webcast will be archived on Modernas website for one year following the presentation.

About Moderna

In 10 years since its inception, Moderna has transformed from a science research-stage company advancing programs in the field of messenger RNA (mRNA), to an enterprise with a diverse clinical portfolio of vaccines and therapeutics across six modalities, a broad intellectual property portfolio in areas including mRNA and lipid nanoparticle formulation, and an integrated manufacturing plant that allows for both clinical and commercial production at scale and at unprecedented speed. Moderna maintains alliances with a broad range of domestic and overseas government and commercial collaborators, which has allowed for the pursuit of both groundbreaking science and rapid scaling of manufacturing. Most recently, Modernas capabilities have come together to allow the authorized use of one of the earliest and most-effective vaccines against the COVID-19 pandemic.

Modernas mRNA platform builds on continuous advances in basic and applied mRNA science, delivery technology and manufacturing, and has allowed the development of therapeutics and vaccines for infectious diseases, immuno-oncology, rare diseases, cardiovascular diseases and auto-immune diseases. Today, 24 development programs are underway across these therapeutic areas, with 14 programs having entered the clinic. Moderna has been named a top biopharmaceutical employer by Science for the past six years. To learn more, visit

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including statements regarding: the potential for delivery of mRNA to hematopoietic stem and progenitor cells (HSPC) in vivo; methods of detecting and interrogating HSPC in vivo; the potential for delivering LNPs to hematopoietic stem cells in vivo; the ability to optimize codons and mRNA structures to increase total protein outputs; the potential for the Company to develop processes for controlling protein expression by modifying ribosomal loads; the Companys ability to engineer LNPs capable of accessing difficult-to-transfect primary cells with efficient endosomal escape and high functional mRNA delivery; the Companys strategy for combatting COVID-19, including processes for monitoring emerging variants and waning immunity; and strategies for modeling viral escape. In some cases, forward-looking statements can be identified by terminology such as will, may, should, could, expects, intends, plans, aims, anticipates, believes, estimates, predicts, potential, continue, or the negative of these terms or other comparable terminology, although not all forward-looking statements contain these words. The forward-looking statements in this press release are neither promises nor guarantees, and you should not place undue reliance on these forward-looking statements because they involve known and unknown risks, uncertainties, and other factors, many of which are beyond Modernas control and which could cause actual results to differ materially from those expressed or implied by these forward-looking statements. These risks, uncertainties, and other factors include, among others: the fact that there has never been a commercial product utilizing mRNA technology approved for use; the fact that the rapid response technology in use by Moderna is still being developed and implemented; the safety, tolerability and efficacy profile of the Moderna COVID-19 Vaccine observed to date may change adversely in ongoing analyses of trial data or subsequent to commercialization; the Moderna COVID-19 Vaccine may prove less effective against variants of the SARS-CoV-2 virus, or the Company may be unsuccessful in developing future versions of its vaccine against these variants; despite having ongoing interactions with the FDA or other regulatory agencies, the FDA or such other regulatory agencies may not agree with the Companys regulatory approval strategies, components of our filings, such as clinical trial designs, conduct and methodologies, or the sufficiency of data submitted; Moderna may encounter delays in meeting manufacturing or supply timelines or disruptions in its distribution plans for the Moderna COVID-19 Vaccine; whether and when any biologics license applications and/or additional emergency use authorization applications may be filed in various jurisdictions and ultimately approved by regulatory authorities; potential adverse impacts due to the global COVID-19 pandemic such as delays in regulatory review, manufacturing and clinical trials, supply chain interruptions, adverse effects on healthcare systems and disruption of the global economy; and those other risks and uncertainties described under the heading Risk Factors in Modernas most recent Annual Report on Form 10-K filed with the U.S. Securities and Exchange Commission (SEC) and in subsequent filings made by Moderna with the SEC, which are available on the SECs website at Except as required by law, Moderna disclaims any intention or responsibility for updating or revising any forward-looking statements contained in this press release in the event of new information, future developments or otherwise. These forward-looking statements are based on Modernas current expectations and speak only as of the date hereof.

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Moderna Highlights Advances in Platform Science and Innovative Vaccine Research at Fourth Annual Science Day - Business Wire

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